Systematized Survey on the History of Drug Discovery withTechnical Development

2
Kohei Umezu

Abstract
This Survey on the Systemization of Industrial Technologies for Medicines systematically investigates
pharmaceutical technologies by tracing the history of the advancement. It starts with crude drugs (natural drugs
derived from minerals, plants, and animal substances), which have been used since the dawn of civilization. Thenmodern science discovered the causes of many diseases, which led to research and development of new medicineswith speciﬁc mechanisms of action to eliminate those causes. Although few crude drugs are used at present, some of
their ingredients are highly eﬀective and others have unique mechanisms of action. These ingredients have made asigniﬁcant contribution to modern pharmaceutical drug discovery as a basis for the advances of various technologies.
This paper consists of three chapters. The second chapter, History of Disease and Medicines, outlines the historyof pharmaceutical drugs used from the earliest civilizations to the present day.
This chapter consists of four sections. The ﬁrst section is History from Ancient to Early Modern Times, whichnarrates the history of crude drugs used together with remedies from witchcraft as well as the ﬁght against
humankind’s greatest enemy, pandemic diseases, in Ancient Mesopotamia, China, and India through Greece andRome to the dawn of modern science.
The second section, The Dawn of Modern Science and Medicine describes how modern science identiﬁed andisolated the active ingredients from crude drugs and the history of new pathogen discovery.
The third section, The Origin of Modern Pharmaceutical Drug discovery and Development explains how basic
sciences including immunology, chemotherapeutics, and pharmacology, have evolved into the modern medical
system for the scientiﬁc drug development. This section also examines the circumstances of the pharmaceuticalindustry in Japan which started behind Western countries.
The fourth section, From New Medicines to Improved Medicines and Innovative Medicines, describes the processof the rapid evolution in Japan of pharmaceutical development after the Second World War using the cases of
β-receptor antagonists and digestive, anti-inﬂammatory, and central nervous system medications as example.
The third chapter, Technological Advancement of Pharmaceutical Drug Discovery and Development through
Systems Science, illustrates the process of drug development and technological innovation driven by advances inscience. In the late 20th century, drug development became too complex to be accomplished just by pharmacologists
and specialists in organic synthesis, evolving into a multidisciplinary science that necessitated a wide range ofexpertise. This process of evolution is also presented in the third chapter.
The fourth chapter discusses the advances of pharmaceutical drug discovery and development from modern times
to the present using the example of lifestyle-related diseases, which have attracted attention as one of the mostcommon health issues in current society. The drugs that have undergone research and development forlifestyle-related diseases are systematized, especially medications for diabetes, hypertension, hyperlipidemia,
thrombosis and clotting disorders, and hyperuricemia.
In addition to drugs for lifestyle-related diseases discussed in this paper, there are numerous medicines available
for a wide range of diseases such as central and peripheral nervous system disorders, cardiovascular diseases, heart
failure, respiratory diseases, urinary tract disorders, hormonal and endocrine disorders, digestive tract disorders,rheumatism and inﬂammation, allergic and immune disorders, sensory disorders, bacterial and viral diseases,
cancers, orphan and rare diseases, and medications such as anesthetics in surgery. The details of these drugs will be
described in other papers.
This paper outlines the history of drug development such as β -receptor antagonists, and digestive, central nervous
system, and anti-inﬂammatory related drugs, as mentioned above, because these were the ﬁrst drugs created by themodern pharmaceutical drug discovery and development system and thus are closely related to advances ofpharmaceutical development technology. This technology has evolved rapidly since the Second World War, and isbecoming an established system at present.
Advancement in genetic engineering has enabled us to utilize the genes of diﬀerent species since around1972.
Application of this biotechnology has opened up the way to develop the biological medicines, which are now growing
in number. This progress is brieﬂy summed up in this paper, and the details such as the antibody medicine will becovered in another opportunity.
This figure (Fig. 0.1) outlines the discussion of the present paper. The history of medicines for infectious diseases
and that of other medicines are shown separately in two chronological ﬂow charts.
Analytical studies on the ingredients of crude drugs started in the 19th century. Afterword, advancements inﬁelds ofsciences such as pharmacology and organic chemistry led to establishment of the pharmaceutical drug discovery anddevelopment process, and a variety of new drugs have been developed, with some being based on theory and somebeing discovered by chance. Researchers ﬁrst tackled the development of simple medicines that were easy todevelop by using pharmaceutical technology, and then gradually expanded their eﬀorts to include medicines forcomplex diseases. After the human genome was ﬁrst mapped in 2000, the attention of researchers has recently
focused on personalized and regenerative medicine.
A scientiﬁc approach to the infectious diseases, involving immunotherapy and chemotherapy, also emerged in the
19th century, when many pathogens were discovered after years of ﬁghting against this enemy. Since the invention of
antibiotics in the-mid 20th century, treatment of infectious diseases has been signiﬁcantly improved, saving countless

lives.
In conclusion, this survey systematizes the technologies for developing medications by tracing the advances fromcrude drugs to scientiﬁc development of modern medicines along with the historical background.

Ancient times

Early modern times

Age of crude drugs

Pathogendiscoveries

Modern times

Immunotherapy

Cinchona

Basis ofchemotherapeut
ic drugsstnd

1 generation

2 generationrd
3 generation

Infectious
diseases
Virus

Chemotherapy drugs
Genomic
drug
Anti-cancer
drugs

Isolation ofingredients

Basis ofpharmacology

Basis of drug
discovery

CancerImmunesystemModern drug
discovery
Pain relief
Anesthesia
Anti-inflammatory

Nightshades
Anesthetic drug

Drugs for surgical diseases

Poppy, coca, ephedra
Drugs for CNS diseases
Crude drug with antipyretic andanalgesic effect: willow

Drugs for gastrointestinal diseases
Crude drugs with laxative, intestine and stomach medication effect:aloe, senna

Psychotropic
Depression
Anxiety

UlcersDiabetes

Drugs for lifestylediseasesHypertension
Hyperlipidemia
Thrombosis/
haemorrhage
Hyperuricemia

Individualized medicine

Regeneration medicine

Fig. 0.1 Composition of Systematized Survey on the History of Drug Discovery with Technical Development.

 ProﬁleKohei Umezu
Chief Survey Officer, Center of the History of Japanese Industrial Technology, National Museum of Nature and Science
1969
1971

1977
1978
1980
1996
2000
2001
2002

2004

2007
2008
2009
2010

Graduated from Kyoto University, Faculty of Pharmaceutical
Sciences
Graduated from Kyoto University, Graduate School of
Pharmaceutical Sciences
Started working for Mitsubishi Chemical Industries, Central
Research Laboratory
Studied at Michigan State University, Department ofPharmacology
Studied at Yale University, Yale School of Medicine, Departmentof Pharmacology
PhD in Pharmacology at Kyoto University
Head of the Product Planning Department, Mitsubishi Chemical
Corporation Pharmaceuticals and Diagnostics Company
Director of Mitsubishi-Tokyo Pharmaceuticals and Director of theMedical Research InstituteExecutive Officer and Director of Research, Mitsubishi Pharma
Corporation
Executive Officer of Mitsubishi Chemical Corporation and
Director of the Healthcare Planning Center, concurrent Director of
Mitsubishi Chemical Safety InstituteManaging Director and Head of the Clinical Trials Department,
Head of the Food Products Division in charge of Research andDevelopment, Mitsubishi Kagaku Bio-Clinical Laboratories
Director and Managing Executive Officer, Head of the Business
Development Office in charge of the Anti-Doping Center
Visiting Professor at Wayo Women’s University
Appointed Consultant to Mitsubishi Chemical Medience
Retired from Mitsubishi Chemical MedienceContents
1. Introduction............................................................ 1
2. History of Disease and Medicines.......................... 3
3. Technological Advancement of Pharmaceutical
Drug Discovery (Drug Discovery as a Systems
Science) .............................................................. 55
4. Detailed Discussion (Lifestyle-Related Diseases) 65
4.1. Medications for Diabetes
4.2. Medications for Hypertension
4.3. Medications for Hyperlipidemia
4.4. Medications for Thrombosis and Clotting
Disorders
4.5. Medications for Gout/Hyperuricemia
5. Conclusion and Acknowledgements .................. 121
Systematic Diagram of Drug Discovery Technology124
Confirmed Location of Historical Resources on
Industrial Technologies for Medicines .................... 128
Chronology of Drug Development .......................... 129

1

Introduction

In 2012, the average life expectancy in Japan was 86.4
years for females and 79.9 years for males. According to the“2010 Annual Changes in Life Expectancy taken from
Complete Life Tables”, a resource produced every five years
by the Ministry of Health, Labour and Welfare based on thenational census, the life expectancy was 42.8 years for males
and 44.3 years for females in the period from 1891 to 1898,
the earliest life table recorded. In the period from 1926 to
1930, the life expectancy was 44.8 years for males and 46.5
years for females. Even by 1935, the life expectancy was still
surprisingly short, at 46.9 years for males and 49.6 years forfemales. By 1955, the figures had risen to 63.6 years formales and 67.8 years for females; by 2010, they had risen to79.6 years for males and 86.3 years for females.
While it is not as straightforward as simply comparing
Meiji-period data with the data of today, this resource does
indicate that there was a rapid increase in life expectancy
after the Second World War, whereas even in the late 1930s
and early 1940s people were not expected to reach 50 yearsof age. To what could this change be attributed? It is a factthat infant mortality is closely tied to life expectancy;
however, the life expectancy only increased by three to four
years in the 44-year period from 1899 to 1935, despite
improvements in hygiene and nutrition accompanying
advances in education from the late 19th century through to
the late 1920s. Alongside these improvements inenvironmental and hygiene conditions, medicine is thought
to have played a significant role in the rapid increase inpost-war life expectancy.
The 2011 “Vital Statistics” by the Ministry of Health,Labour and Welfare record the mortality rates by leading
causes of death from 1899 to 2009 (Figure 1.1). The
mortality rates for the 110-year period shown in this diagram
indicate a significant change on either side of the blankperiod representing the Second World War (Pacific War).
The top three leading causes of death before the war werepneumonia, gastroenteritis and tuberculosis, followed by
cerebrovascular diseases (cerebral hemorrhage, stroke).
Given that the top three leading causes of death were
infectious diseases, with gastroenteritis encompassing
diseases such as cholera, typhoid fever, dysentery anddiarrhea, it is evident that the mortality rate from infectious
diseases was extremely high.
After the war, there was a rapid decrease in the mortality
rate from these types of infectious diseases. This underlines
the importance of improved hygiene and nutrition conditions,as well as the emergence of antibiotics and antibacterial
medicines. With the arrival of penicillin to combat infection,
as well as streptomycin, p-aminosalicylate (PAS) andisoniazid, among others, to combat tuberculosis, the change
in mortality rates demonstrated the ground-breaking efficacyof these medicines. Thus, the life expectancy in Japan began
to increase after the war. Second- and third-generation
antibiotics and antibacterial medicines became the mainstayof the Japanese pharmaceutical industry and stayed that way

for a long time. With the infectious diseases that had been
the top leading causes of death now able to be remedied,cerebrovascular diseases became the top leading causes ofdeath. Since at that time there were no refrigerators as yet,the Japanese were using large quantities of salt in homemademiso and pickles that could last up to six months. These highamounts of salt are believed to have been a leading cause of
hypertension in those who were eating these products on adaily basis. Epidemiological and medical studies eventually
identified a link between hypertension and cerebrovasculardiseases and people began to realize how important it is forordinary individuals to take steps to lower their bloodpressure. A series of blood pressure medications began to be
developed to reduce blood pressure using pharmacologicalaction mechanisms; as blood pressure was brought underproper control, the number of people suffering from
cerebrovascular diseases declined. Blood pressure
medications played a significant role in reducing the
mortality rate from these diseases.
Stomach ulcers and duodenal ulcers had been incurable inJapan since the late 19th century; even after the war, theyrequired surgery. The discovery of H2-receptor antagonist
oral drugs improved treatment efficacy to the point where
surgery was no longer required. Meanwhile, as the economy
developed and lifestyles became more stable with adequate
food and clothing, there was a gradual increase inlifestyle-related diseases. In the coming era, diabetes,
hyperlipidemia, obesity and other lifestyle-related diseases
began to draw attention. The so-called “metabolic syndrome”
exacerbated the hardening of the arteries and insulin
resistance, ultimately leading to ischemic heart disease or
cerebrovascular disease. A succession of hyperlipidemia
medications and cholesterol-lowering medications began to
be developed, as a major cause of hardened arteries isexcessive cholesterol or triglycerides in the blood. Statins, aclass of cholesterol-lowering medications invented in Japan,
demonstrated a powerful efficacy, receiving worldwide
acclaim as a breakthrough drug, and made a significant
contribution to reducing ischemic heart disease. Several
other new drugs developed in Japan have also produced goodresults as diabetes medications, anticoagulants andantiplatelet drugs.
Despite growing public awareness, we have entered anage of fine dining and insufficient exercise. Since 2007, theMinistry of Health, Labour and Welfare has implemented
specific physical examinations as a countermeasure against
metabolic syndrome, attempting to raise greater publicawareness and also reduce ever-increasing medical expenses,
but the result thus far has been less than satisfactory.
Nevertheless, inadequate as it may be, education and new
drugs also have some effect; the increase in mortality rate
due to lifestyle-related diseases is no longer as rapid as it
once was.
Meanwhile, the leading cause of death shifted to cancer(malignant neoplasm) from around 1980. Unlike infectious

Systematized Survey on the History of Drug Discovery with Technical Development1diseases, cancers are not caused by microbes from outside
the body, but by changes in the body’s own cells. Advances
in molecular biology and genetic engineering have made it
evident that not all cancers are the same and that they havedifferent properties when manifesting in different organs, aswell as that anticancer medications react differently in
different individuals, so that one medication is not effective
against all cancers. We have now entered an era of ongoing
research and development on medications for different
cancers, or anticancer medications that target individual
genes and genetic makeups.
Although medications have played an extremely
significant role in maintaining healthy lives for people
amidst these changing times, they in fact have quite a shorthistory; it has only been since the end of the Second World
War that theoretically and scientifically effective
medications have come to be produced.
This survey report retraces the history of medications fordiseases suffered by humans and provides a systematic
examination of developments in pharmaceutical technologies,
from the crude drugs and remedies from witchcraft in ancient
times to the drug discoveries of today supported by modern
science. The hope is that this will serve as a reference
resource for the next generation of young technologists andresearchers in looking back at the steps taken by the pioneers
in the industry and thereby play a role in future
pharmaceutical research and development.

Long-Term Trends (-2010) in Mortality Rates by Leading Causes of Death (per 100,000)

Pneumonia

Gastroenteritis

Malignant neoplasm

Tuberculosis

Cerebrovascular diseases

Heart disease

Old ageAccidents
SuicideDiabetes(Note) The decline in heart disease in 1994 is thought to be due to advance awareness of a cautionary statement
to be added to new death certificates (post-mortem certificates) (implemented January 1, 1995) advising not
to enter heart failure or respiratory failure in the cause-of-death column as the terminal phase of thedisease. The more recent years are approximate figures.
(Source) Ministry of Health, Labour and Welfare “Vital Statistics”

Fig. 1.1 Mortality Rates in Japan by Leading Causes of Death

2

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March2

History of Disease and Medicines

Chapter 2 outlines the history of diseases suffered byhumans and the medications used to combat them.
The first section of this chapter discusses human history
from ancient to early modern times as the age of using
natural products (crude drugs) and provides a summary of
those crude drugs as well as the diseases most feared at eachpoint in time. The next section discusses the dawn of modern
science and medicine as the age of advances in organic
synthetic chemistry and isolating and identifying ingredients,
in which modern science began and the main substances(drugs) in natural products started being extracted, isolated
and identified, and infection-causing pathogens started being
identified. The following section discusses the origin ofmodern pharmaceutical drug discovery and development, inwhich developments in pharmacology and biochemistry
made it possible to start analyzing the actions mechanisms ofdrugs, through to modern drug discovery supplemented bysynthesis technology based on organic chemistry. The final
section in the chapter examines the evolution of drugs andthe advances in drug discovery from new medicines toimproved medicines and innovative medicines, discussing
successive discoveries of new drugs since the Second World
War, aided by modern drug discovery technology, through tothe age of the so-called genomic drug discovery from the late
1990s onwards.

2.1 History from Ancient to Early Modern Times(Age of Using Crude Drugs)
2.1.1.

History of Drugs (Ancient Times to 19th
Century )Living in ancient times before agriculture, our ancestors
would have been desperate to secure food for survival. They
would have eaten whatever plants or animals they could get
their hands on, and through their experiences would haveclassified these as edible or inedible, having inevitably comeinto contact with poison at some point, experienced foodpoisoning from eating decomposing matter and suffered from
infectious diseases. During that process, they would havecome to know that certain plants, animals or minerals wereeffective at relieving pain and fever. They would have alsocome to know how to make use of plants that cause vomitingor diarrhea, and would have passed this information on totheir descendants. Eventually, people started planned hunting
in groups as well as learning how to farm; over a long periodof time, ancient civilizations were born.
As these ancient civilizations developed in various places
around the world, people started accumulating andsystematizing their knowledge of drugs (crude drugs) derived
from natural plant, animal and mineral substances. Usage ofthese crude drugs including grinding and extracting by
mixing with hot or cold water, drying and eating, andapplying to the affected area as a paste.
Around 5000 BP in Mesopotamia, the Sumerians arereported to have engraved the names of various medicinal
animals, plants and minerals on clay tablets in cuneiform.

Medical treatment in this region at that time was intertwinedwith astrology; people believed that everything, including thefate of humans, was determined by the movement of the stars,
which represented the will of the gods. These clay tablets,
together with some slightly more recent clay tablets, record
more than 250 species of plants, more than 180 species ofanimals and more than 120 kinds of minerals used for crude
drugs. Poppy and henbane were used to relieve pain,
cinnamon for gastronomical problems, pomegranate for
expelling parasitic worms and almonds and licorice forsuppressing coughs. These drugs were not used on their own,
but were combined in close connection with incantations andwitchcraft (1).
This information was passed on to the Egyptians andeventually compiled together. The Ebers Papyrus, a medical
compendium written in the 13th Egyptian dynasty around3500 BP, records 700 types of crude drugs, including
medications for wounds, skin diseases, women’s diseases,
laxatives and emetics. The curing of diseases usually
involved the driving out of demons of sickness dwelling
inside the body, often through the prescribing of emetics,
laxatives or enemas. In some cases, animal dung, rotting
flesh or fat was used to achieve this. A number of otherpapyri have been discovered with crude drugs recorded inthem, although they are from other eras (1).
Hippocrates, who lived in the fifth and fourth centuries
BCE, was a representative physician of the Classical Greek
era; his ideas are still highly valued to this day. One of his
greatest achievements was separating medicine fromprimitive superstitions and witchcraft and developing it into
an empirical science with high regard for clinical practiceand observation. Assuming that diseases were some kind ofnatural disorder, he emphasized the use of medicine to assist
the natural healing power of the body. He is said to havetreated patients with only limited drugs, such as laxatives,
emetics and diuretics.
Some of these ideas have been carried through intomodern medical and pharmaceutical science, which is why
Hippocrates is referred to as the “father of modern medicine”.
A text entitled The Oath, regarding the morality andobjectivity of physicians, is included among his collected
works; this has been carried down to the present day as the
Hippocratic Oath.
Medications used at the time included milk or oriental
melons as laxatives, sodium carbonate or honey for enemas,
a mixture of honey and vinegar as an emetic and spring
onions or sea onions as diuretics. Imperial Rome imported
valuable drugs and Oriental medicines from across the vast
expanse of its occupied territories and many complicatedformulations of crude drugs were invented (1, 2, 3).
The first century CE brought Pedanius Dioscorides,
known as the world’s first pharmacologist (4). His
five-volume Materia Medica, the world’s first scientificwork on pharmacognosy and pharmacology, lists 600 typesof drugs and records the habitats, proper names andalternative names of medicinal plants, as well as accurate

Systematized Survey on the History of Drug Discovery with Technical Development3

sketches of them.
Medication therapy was popular in Imperial Rome,leading to a chaotic state of disarray as various different
factions of medicine emerged alongside growing numbers of
traders in counterfeit medicines. The second century brought
Claudius Galenus, known as Galen, whose adherence to the
Hippocratic notion of the natural healing power of the bodyled to a revival of Hippocratic medicine. Galen is believed tohave authored over 500 treatises on an expansive range of
topics, including anatomy, physiology, etiology, pathology,
diagnoses and treatments. In the field of pharmacology, herecorded different types of drugs, their effects and theirformulation. While Galen made some significant
achievements in the development of contemporary medicine,
his works are permeated with his own views and biases.
However, Galen’s works on medicine remained theauthoritative works on the subject throughout the Middle
Ages to the Renaissance; under the domination of theseauthoritative works, an age of no significant medical
discoveries or inventions continued. Later generations ofpharmacologists continued to term their own herbal
preparations as Galenic formulations, even into early modern
times, in an attempt to benefit from Galen’s authority, evenwhen those formulations contradicted Galen’s works.
Three million people are said to have died in the Crusades,
these heavy casualties occurring in the Dark Ages before thedevelopment of science. While universities started being
established in various places throughout Europe from the 12th
century onwards, the university in Bologna became famousfor surgical medicine.
However, surgical procedures date back to ancient times.
The Sumerians are believed to have had the technology fortrephining and removing tumors. Human dissections are
believed to have been carried out in Imperial Alexandria,
accompanied by advancements in surgical techniques, suchas performing surgical operations using an infusion ofmandragora as an anesthetic. The revival of surgical
techniques in the 12th century included the use of the sap
from medicinal plants as an anesthetic. Human dissection,
which had not been practiced since the Alexandrian era,
revived in 1302 for medical research purposes. The
foundation for the systematic study of anatomy was laid by
Mondino de Luzzi in his 14th century work Anathomia
corporis humani (2, 3, 5).
Pharmacists and pharmacies were coming into being
throughout Europe from the 11th to the 14th centuries. The
study of anatomy had developed to the point of noting errors
in Galen’s works, but his authority had yet to be contested.
Andreas Vesalius, regarded as the founder of anatomy, issaid to have caused an uproar in scientific circles in 1543
with his publication of De humani corporis fabrica, the firstwork on human anatomy (1:94-96).
Retracing the history of crude drugs reveals that they havebeen used since ancient times the entire world over in
conjunction with witchcraft. While in many cases these crude
drugs would have been of dubious effectiveness in and ofthemselves, in some cases as modern science has isolated theactive ingredients it has shown that there was a rational
reason for their usage, with an empirically proven medicinal
effect, such as opium from poppies or henbane andbelladonna in the nightshade family. Crude drugs from all

4kinds of natural products would have been tested to try to
alleviate pain, cramps and fevers from acute illnesses,
empirically showing which ones had a strong medicinal
efficacy. However, while crude drugs with strong medicinal
efficacy could alleviate pain or cramps, there would havebeen very little progress made in terms of causal therapy totake effect on the cause of the ailment.
Surgical techniques have been practiced since ancient
times. Although crude drugs with strong medicinal efficacy
were also used since the very early days, the anesthesia effectwas not the same as that used in modern medicine, often
involving widespread paralysis of the central nervous system.
The study of anatomy was essential, not only for surgical
techniques, but also for the development of medical science;
however, it was strongly discouraged in an era in which
religion and medicine were intertwined.
The oldest work on Chinese medicine is the Rites of Zhou,
complied by Duke Wen of Zhou around the 3rd or 4th century
BCE. Although primarily written about the government
system of the Zhou Dynasty, it mentions a technique used bydoctors involving “five poisons and five medicines”. The“five medicines” are grass, wood, corn, stone and insects,
while the “five poisons” are mineral poisons. This idea wasalso carried over into The Devine Farmer’s Classic ofMateria Medica, the oldest work on herbal medicines,
written in the Three Kingdoms period of China (3rd centuryCE). Although the author of this work is unknown and theoriginal text has been lost, Tao Hongjing of the Liang
Dynasty compiled his three-volume Reading of the Divine
Farmer’s Classic of Materia Medica around 500 CE basedon this work and later a further seven-volume edition. These
works record more 730 types of medicines.
Of the medicines recorded in The Divine Farmer’s Classicof Materia Medica, 365 are categorized three ways into thenoble or upper herbs, the commoner or middle herbs and thelower herbs. The 120 upper herbs are designated as non-toxic,
life-enhancing drugs that can aid longevity, able to be taken
long term. The 120 middle herbs are designated ashealth-enhancing drugs, some non-toxic and some toxic. The
125 lower herbs are designated as treatment drugs, but highly
toxic and not able to take long term. In Chinese medicine,
medicinal herbs are not determined on the efficacy of theherb in and of itself, but on the idea of interaction, so thatcertain effects are achieved through certain combinations (6,7).
Archaeological findings at ancient Indus Valley
Civilization sites discovered in the lower reaches of the Indus
River indicate that there was quite a highly advanced ancientcivilization in this region around 5000 years ago.
The Brahma sutras were compiled around 3500 years ago.
One of these, the Ayer Veda, suggests that a traditional
medical system was established around 3000 years BP. This
work categorizes medicine into eight different disciplines,
including surgery, internal medicine, pediatrics andpsychiatry. Treatment methods include “taking and vomiting
medicine”, “cleansing the intestines using diarrhea or an
enema” and “blood-letting at bad points”. Crude drugs wereused in complex combinations and in large quantities. The
idea was that “there is nothing that exists on the earth thatcannot be used as medicine”. A medical treatise written by
Sushruta, a 4th-century Indian physician records in detail

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchvarious animal toxins found in tropical environments, such as
in snakes and frogs, as well as methods for counteracting
those poisons (8, 9).
There are thought to be more than 2000 different kinds of
crude drugs found around the world; other than someregional variations, there are no significant fundamental
differences between the crude drugs found in different
regions.
In Japan, according to Kojiki and Nihon Shoki,
Takamimusubi, one of the three deities of creation, is reveredas the god of medicine. His son, Sukuna-Biko-Na, worked
together with Ōnamuchi-no-mikoto, known for healing theHare of Inaba, to try to treat the diseases of humankind in ademonstration of divine virtue (10). As in other parts of theancient world, illness in ancient Japan was the work of gods
and devils and witchcraft was a principal method of medical
treatment. As in other ancient civilizations, crude drugs wereused experimentally as an added measure.
From the 4th century onwards, as the Yamato Imperial
Court began to have increasingly more exchange with the
Korean Peninsula, medical and pharmaceutical science fromthe Asian continent began to spread to Japan. In 553,
Emperor Kimmei sent an envoy to Baekje requesting Beon
Yangpung and Jeong Yuta be sent to Japan as experts inmedicinal herbs. In 563, Chiso of Wu was naturalized andpresented the emperor with 164 books, including works on
Chinese medicine.
Shitennōji Temple was constructed during the reign ofEmpress Suiko and incorporated a dispensing apothecary,
where medicinal herbs were cultivated. Zenna, the son of
Chiso of Wu, who had gifted Emperor Koutoku with milk, isregarded as the father of medication production in Japan.
Systematically produced medicines were imported toJapan by envoys to the Sui and Tang Dynasties of China.
Chinese monk Jianzhen finally reached Japan on his sixth
attempted voyage at the invitation of Emperor Shoumu,
bringing Buddhism with him, as well as many medicines.
Around 60 of those medicines from that time still exist andare held among the artifacts at the Shōsō-in treasure house in
Nara, cataloged as “various pharmaceuticals”. In the late
1940s, Yasuhiko Asahina led an investigation on the
medicines held at the Shōsō-in. The study confirmed theexistence of 29 types of medicine and determined that mostof these were imported products (11:45-47, 12:337-338).
As Tang Dynasty medical science began to be introduced
to Japan with the sending and receiving of envoys, Korean
medicine gradually began to go to into decline in Japan andwas completely overtaken by Chinese medicine by the Edo
Period.
Japanese Names of Medical Herbs, written in the Heian
Period, lists 1025 types of medicines and is thought to be
Japan’s oldest book on medicinal herbs. While many of the
medicines are also recorded in the contemporary work
Ishinpō, the content draws references from Korean medical
works and The Newly Revised Pharmacopeia from Tang
China.
The battles throughout the Kamakura andAzuchi-Momoyama Periods prompted the development of
medicines to treat wounds. The arrival of Western culture in
the 16th century brought surgical techniques and Galenic
medicine, discussed above. However, the main external

medicines were ointments for cleaning wounds, salves andcompress pastes (13).
The more stabilized society of the Edo Period ushered in a
golden age of medical and pharmaceutical products. A
uniquely Japanese branch of “experimental Chinese
medicine” began to flourish, known as Kampo medicine.
This was founded by Chinese medical practitioner Todo
Yoshimasu based on the Treatise on Cold Injury, compiled
by Zhang Zhongjing in the Later Han Dynasty. Everyday
people were buying medicines, ranging from medicinal
plants bought from the medicine vendors of Toyama to
medications bought from drug wholesalers, while doctors
were referring to The Divine Farmer’s Classic of Materia
Medica, the Compendium of Materia Medica written by Li
Shizhen and other classic Chinese medical texts to formulate
their own medications and dispensing these to their patients.
Edo-Period medicines were also known as Tang medicine,since many of them were imported from China. Syphilis,
tuberculosis and leprosy were rampant during this time.
Sarsaparilla root was often used to treat syphilis, while
ginseng or cinnamon was used to treat tuberculosis andchaulmoogra was used to treat leprosy. The earliest record ofsyphilis in Japan is found in the medical treatise Gekkai Roku,
written by Shūkei Takeda in 1512. In the Edo Period,
Dokushōan Nagatomi, a well-traveled doctor, wrote thateight out of ten invalids in Edo, Nagasaki and Osaka were
suffering from syphilis (15:25). The biggest Chinese medicine
import during the Edo Period was sarsaparilla root; the factthat it was used to treat syphilis indicates how rampantsyphilis was at the time. It was later replaced by a similar
species of sarsaparilla grown in Japan (14).
The Latest Reports on Pharmacology by Tatuo Kariyone
records that “sarsaparilla root was formerly used as analternative against syphilis and rheumatism, but now hasvery little medicinal use” (16). Syphilis is caused by infection
from Treponema pallidum bacteria; no substance found insarsaparilla root has been identified as having any properties
that have any effect on the Treponema pallidum bacteria.
The three main infectious diseases were dysentery,typhoid fever and cholera. Although rhubarb, Chinese
ephedra, Baikal skullcap, licorice and dried aconite root wereused to treat these diseases, it is presumed that these crude
drugs probably had no direct bacteria-killing effect.
An examination of crude drugs around the world fromancient civilizations through to early modern times reveals
that during the several millennia before modern science
identified the causes of diseases and the action mechanismsof the drugs needed to treat them, natural plant, animal andmineral products were used medicinally alongside witchcraft
and religion all the world over, although there was much incommon among the natural products used.
Although it is difficult to categorize those diseases fromthe perspective of modern medicine, they can be categorized
by crude drug usage. The following discusses: (i)medications for digestive system diseases; (ii) medications
for diseases causing pain, fever or cramps; (iii) medications
relating to surgical procedures, such as treating wounds orremoving tumors; (iv) medications for infectious diseases;and (v) medications for lifestyle-related diseases, such as
diabetes and arteriosclerosis.

Systematized Survey on the History of Drug Discovery with Technical Development

5(i) Throughout the ancient world, the cause of diseases
was beyond human understanding. A common idea all
around the world was the use of cathartics, laxatives orvomiting/diarrhea-inducing drugs to expel the disease fromthe body. Although the prescriptions used to rid patients of
diseases were not always theoretically consistent with thecause of disease, this method presumably would haveworked to expel toxins from the body in the case of foodpoisoning or accidental ingestion of poison. It may also havebeen effective to some extent in the case of infectious
diseases affecting the digestive system.
While there are many crude drugs that can benefit a
stomach affected by minor ailments of the digestive system,
the placebo effect also cannot be overlooked, as shall bementioned later.
(ii) Fevers, pains and cramps caused by infectious diseases
and various other diseases suffered by humans could
presumably have been eased by crude drugs such as willow
bark, which has an antipyretic and analgesic effect, or bynerve paralysis using plants in the nightshade family thatstrongly affect the central nervous system, or in modern
pharmacological terms, have an acetylcholine-like effect oranti-acetylcholine-like effect. Poppies and ergot fungi, which
induce mental exhilaration, were also presumably used forpain control in the treatment of various diseases. However,the use of crude drugs with strong neurological effects would
surely have also caused some major side effects in patients.
(iii) Since ancient times, wounds have been commonplacein battle and in everyday life. While medicated pastes andsometimes surgery were used to treat wounds, there was noconcept of sterilization until more recent times. As discussed
in (ii), crude drugs with strong neurological effects wereused to alleviate pain and inflammation.
There are ancient records from all over the world oftumors also being removed by surgery. The idea has existed
since ancient times that the body will return to normal after
removing a tumor or damaged tissue. However, although
crude drugs were used, none of them would have had a verystrong anti-inflammatory effect. Records indicate thatnightshades and poppies containing morphine and codeine
were used for analgesia and as a substitute anesthetic.
In Japan, when surgical techniques developed in the
Azuchi-Momoyama Period, serious wounds were bound up
to prevent bleeding and smelling salts (stimulants)
administered. Styptics were used to stop bleeding andwounds were cleansed with ointments. Cuts in muscle tissue
and broken bones were dressed and splinted; arrows andbullets were removed with the aid of medications (5).
However, it stands to question what the life extension rate
was among patients treated by surgery in an age in which
there was no concept of disinfection or sterilization. Only
those with strong natural healing power would havesurvived; even then the prognosis would have been
extremely poor.

6

The various effects of early crude drugs presumably often
included a placebo effect (Note 1). Given that the placebo effectis surprisingly strong even in modern medicine, it must havebeen far greater when combined with witchcraft to treat
patients in ancient and medieval times.
Hippocrates shrewdly observes that “clinical symptoms
are natural reactions to a disease, and a temperature isnothing more than this reaction; the natural power given to
individuals is to progress towards treatment and fight against
disease” and that “it is nature that heals diseases; the humanbody has been given natural healing power. The art of
medicine is to aid this; that is the fundamental method oftreatment” (17). This natural healing probably also includes amental placebo effect.
Although there are still many cases today in which astrong placebo effect appears during drug therapy at acutestages, there is also a theory supported by meta-analysis (Note2)
that the placebo effect disappears with long-term
administration and that it cannot be used as a primary formof treatment (18). There are a number of reports on the“magnitude of the placebo effect”. According to a report (19)
put together by the Japanese Society of Gastroenterology,“Beecher’s oft-cited paper (20) reports that the placebo effectimproved post-operative pain and coughing by an average of
35.2±2% in 15 tests”. In a 1994 article, Kienle notes that thereviews on the placebo effect include a report indicating amore than 90% improvement for stomach/duodenal ulcers.
However, Kienle also states that there is no basis for the
purported magnitude of natural healing caused by theplacebo effect alone (21). Clinical trials to evaluate theefficacy of a drug are carried out using the same drug indifferent places around the world; however, reports indicatethat the placebo effect differs significantly depending on theregion and the time (22).
The findings from these current reports reveal that theplacebo effect is very wide ranging and can surprisingly be
as high as 80-90% effective on certain ailments.
Meanwhile, papers that question the placebo effect reveal
a higher placebo effect in tests conducted with fewer people
in the placebo group and a lower placebo effect as the groupsize increases. Further, although some subjective effects arerecognized, it has a lower effect on objective indicators (17).
There has been much recent discussion on the benefits ofplacebos in terms of the ethical aspects of clinical trials (Note 3).
There is also thought to be a need to continue to analyze thescientific efficacy of the effect in diseases susceptible to it
and to consider utilizing the effect. It would not be denying
the historical contribution made by the crude drugs of thepast to include the placebo effect among the effects of those
crude drugs. Meanwhile, it also cannot be denied that thisplacebo effect that is found only in humans may have been
one of the reasons that kept us from discovering truly
effective crude drugs until relatively recently in our history.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

(iv) There are countless different kinds of infectious
diseases. They are able to take large numbers of human lives
at a time and have caused pandemics many times all aroundthe world. Although various crude drugs would have beenused alongside witchcraft and surgical procedures to treat
these diseases and drive out the demons, none of these crude
drugs would have provided any miracle cure. It is now
known that certain fungi have powerful antibacterial
properties, but there is no record of this effect being utilized
until modern times.
Before the causes of dreaded infectious diseases had been
discovered and with no knowledge of how to prevent them,treatment would have simply involved waiting for the patient
to recover naturally. It was not until the 20th century thatsalvarsan, sulfonamides, penicillin and other treatment drugs
appeared. However, it does seem strange that our humanancestors did not encounter “blue mold”, as they must havetrialed thousands or even tens of thousands of different
animal, plant and mineral products as medications.
(v) Based on ancient records and artifacts found atarcheological sites, lifestyle-related diseases such asarteriosclerosis and diabetes are presumed to have existed
since ancient times, although the causes of these diseases
were not identified until the 20th century. Before that, people
with hyperlipidemia, hypertension, arteriosclerosis or other“silent diseases” would have died from heart attack or stroke
without even knowing they were sick. They probably had nofear of lifestyle-related diseases.
The age of experimental treatment methods passed down
since ancient times was a long era in human history. The
dawn of modern science ushered in a significant qualitativechange in medicine.
Note 1: An effect produced by a placebo drug made from ingredientsthat should not have any effect.
Note 2: Meta-analysis: a method of gathering and performing
comprehensive statistical analysis on the results of multiple
separately-conducted comparative randomized clinical trials. There
are pros and cons to this analysis.
Note 3: There is ongoing debate on the ethical issue of dividing
patients in clinical trials into two groups and not actuallyadministering medicine to the placebo group.

References[1] Ishizaka T.: Kusuri no Rekishi (History of Medicine).
Nippon Hyoron Sha (1979).
[2] Matsui J.: Kusuri no Bunkashi (Cultural History ofMedicine). Maruzen Library (1991).
[3] Singer C. & Underwood E., Sakai S. & Fukase Y.
(trans.): Igaku no Rekishi (A Short History of Medicine)Vol. 2. Asakura Publishing Co. (1986).
[4] Ōtsuki S.: Diosukoraidesu Kenkyū (Research on
Dioscorides). Enterprise (1983).

[5] Amano H.: Kusuri no Rekishi (History of Medicine).
Yakuji Nippo (2000).
[6] Ōtuska Y.: Kampō to Kusuri no Hanashi (About
Chinese Medicine and Western Medicine). Shibunkaku(1994).
[7] Okazaki K.: Kusuri no Rekishi (History of Medicine).
Kodansha 21-26 (1976).
[8] Yamazaki M.: Doku to Kusuri (Poison and Medicine).
Nihonbungeisha (2004).
[9] Mikage M. & Kimura M.: Dentō Iyakugaku /Shōyakugaku (Traditional Medicine/Pharmacognosy).
Nankodo 13-20 (2009).
[10] Nemoto S.: Nihon no Yakugaku (Pharmaceutics inJapan). Nankodo 9-12 (1981).
[11] Sakai S.: Yamai ga Kataru Nihonshi (The History ofJapan as seen from Diseases). Kodansha 45-47 (2002).
[12] Nihon Yakugakukai Hyakunenshi (100-year History of
the Pharmaceutical Society of Japan). The
Pharmaceutical Society of Japan 337-338 (1980).
[13] Sekimizu Y.: Kusuri no Rūtsu Shōyaku (Roots ofMedicine: Herbal Medicine). Gijutsu-Hyohron (2010).
[14] Habu K.: Edo Jidai, Kampō no Rekishi (Edo Period:
History of Traditional Chinese Medicine). Seibundo
93-100 (2010).
[15] Sakai S.: E de Yomu Edo no Yamai to Yōjō (Disease and
Health Care during Edo Period in Pictures). Kodansha(2003).
[16] Kariyone T.: Saishin Shōyakugaku (Latest
Pharmacognosy). Hirokawa-Shoten (1965).
[17] Singer C. & Underwood E., Sakai S. & Fukase Y.
(trans.): Igaku no Rekishi (A Short History of Medicine)Vol. 1. Asakura Publishing Co. 27-40 (1985).
[18] Hrobjartsson A, Gotzsche PC.: Is the placebo
powerless? An analysis of clinical trial comparing
placebo with no treatment. New England Journal of
Medicine 344 (21): 1594-1602 (2001).
[19] Japan Society of Gastroenterology Ethics Committee(sup. ed.), Nakamura T. & Terano A. (eds.). Yakuzai
Chiken ni okeru Purasēbo (Placebo in Drug Trials).
Society Publishing Center (1998).
[20] Beecher H. K.: Journal of American Medicine
Association 159: 1602-1606 (1955).
[21] Kienle, G. S, & Kiene, H.: Placebo effect and placebo concept: a critical methodological and conceptual
analysis of reports on the magnitude of the placebo
effect. Alternative Therapies in Health and Medicine 2:
39-54. (1996).
[22] Winship D. H.: Cimetidine in the treatment of duodenal
ulcer. Review and Commentary. Gastroenterology 74:
402-406 (1978).

Systematized Survey on the History of Drug Discovery with Technical Development

7

2.1.2.

History of Infectious Diseases (ancient times –th
19 century)
Infectious diseases claimed countless human lives fromancient to medieval times. In ancient times, there would havebeen fewer opportunities for contact between clans andtherefore less widespread contagion of infectious diseases(pandemics). As civilizations advanced, there was greater
exchange of people and goods, which also meant increased
opportunities for people to come into contact with infectious
diseases. Infectious diseases began to spread with theadvancement of civilization, rapidly broadening the extent of
the harm caused by them.
The following examines the main infectious diseases andtheir histories.
Bubonic Plague
Bubonic plague (Black Death) is an invasive systemic
infectious disease caused by Gram-negative bacillus Yersinia
pestis. It is transmitted by fleas and also through airborne
transmission. In the majority of cases of bubonic plague inhumans, the bacteria spread to the regional lymph nodes,
causing necrosis and boils. It then spreads to the liver, lungs
and bone marrow via the lymph and the blood, causing
septicemia.
Bubonic plague has a very long history. Detailed
descriptions of it have been found in Egyptian papyri dating
to 4300 BP, as well as in the classic Romance of Sinuhe. The
plague bacillus Yersinia pestis has also been found in thelungs and liver of ancient Egyptian mummies. A papyrus
records that when the plague broke out in an ancient
Egyptian stone quarry, the place was quarantined off until
everyone in it had died. Of the pandemics found in recorded
history, the earliest widespread contagion of an infectious
disease presumed to be bubonic plague broke out in the
Eastern Roman Empire (Byzantine Empire) in 542-543 CE.
There was an outbreak of bubonic plague in China fromaround 1320 to 1330; it also spread throughout the Islamic
world during the Mamluk Sultanate, around the same time as
it came to Europe. Records indicate that more than one thirdof the population of Europe was lost to bubonic plague in the
14th century. This is a fearsome story. The flourishing trade
between east and west on the Eurasian continent under thecontrol of the Mongol Empire is believed to be one of theunderlying factors for this pandemic; the danger of infectious
diseases in an age without antibiotics is well known (1:97-132,
2:32-36). There are no accounts of bubonic plague spreading toJapan until 1899, when bubonic plague was spreading
throughout Asia. In 1896, Shibasaburō Kitasato, president of
the Institute for Infectious Diseases, and Tanemichi Aoyama,
professor of internal medicine at Tokyo Imperial University
Medical College, were sent to Hong Kong to research
prevention methods. Kitasato discovered the plague bacillus
Yersinia pestis in 1896 (3:220-221). There is no record of any
bubonic plague patients in Japan after 1926.

8

Malaria
Malaria is a chronic disease caused by the protozoan
Plasmodium, carried by mosquitoes of the genus Anopheles.
Symptoms manifest in the form of sudden violent shaking
accompanied by fever, headache and nausea. This continues
for four to five hours, after which the temperature returns tonormal for two or three days, then the symptoms return. In
severe cases, it can cause impaired consciousness, kidney
failure and death.
Malaria appears in ancient records from China and otherplaces in Asia. The Atharvaveda, compiled in India around3500 BP, records a ritual for a malaria curse, while a bronze
inscription from Yin Dynasty China dating to 1400 BCE
contains a character signifying “malarial fever”. The armies
of ancient Greece also had trouble with malaria, although thetropical coastal areas of the Mediterranean were not the only
endemic areas for malaria, as the low-humidity areas ofsoutheastern England were similarly afflicted (1:133-172). In
1902, English doctor Ronald Ross was awarded the Nobel
Prize in Physiology or Medicine for being the first to
discover the protozoan Plasmodium in the alimentary canalof Anopheles mosquitoes.
Malaria long went without a remedy. Around 1640, plantsof the genus Cinchona, native to the South American Andes,
were imported to Europe as a specific medicine for malaria.
However, it was not until 1820 that a substance known as
quinine was isolated from Cinchona bark for use as a
specific medicine for malaria.
Ancient Japanese records make frequent mention of adisease described as malarial fever; this is thought to be thesame disease as present-day malaria. The character used inJapanese for malarial fever appears in the Taiho Code. It
would seem that malaria has been common in Japan sinceancient times. Records reveal that Kujou Kanezane, author of
Gyokuyō, Fujiwara no Teika, author of Meigetsuki, and even
Taira no Kiyomori suffered from malaria (3:74-76). The disease
was prevalent in the low wetlands of Western Japan until
early modern times, but has been less prevalent since the
Meiji Period.
Smallpox
Smallpox (variola) was a fearsome disease from ancient toearly modern times, with no means of treatment. Due to its
high mortality rate and the fact that survivors were left withscars, it has been one of the most feared infectious diseases
all the world over. Caused by the variola virus and with avery high mortality rate, symptoms include fever, vomiting,lower back pain and rash all over the body. It appears to havebeen affecting humans for the past 10,000 years, withsmallpox pockmarks even noted on the faces of Egyptianmummies (4).
The unfortunate story is well known of Francisco Pizarro
bringing the virus to the Americas during Spain’s invasion of
the South American continent in the 16th century anddecimating the indigenous Incan population, who had no

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchimmunity to the disease. Other records include that of an
outbreak in India in 1770 that claimed three million lives.
Meanwhile, it was discovered at various places around theworld that people could become immune to smallpox.
Without knowing the scientific basis for it, people all over
the world, including Persian nomads and inhabitants of India,
China and the Georgia region of Russia, were inoculating
healthy people with pus taken from an infected person tocause a mild onset of the disease and thereby making them
immune to it. In the late 18th century, it was found thatpeople who had contracted the bovine disease cow pox(humans could contract it, but it was mild and left noscarring) would not contract smallpox. This led to thedevelopment of a smallpox vaccine by Edward Jenner in1796 (5).
Japan had its own outbreak of smallpox during the Nara
Period. This smallpox outbreak, which started in 737, wasthe most dreadful disease that ancient Japan had experienced.
It spread across the entire country from Chikushi in Fukuoka
to the ancient capital of Nara, taking countless lives, as thepeople had no immunity to it. That same year, the disease
took the lives of all four sons of Fujiwara no Fuhito, who had
been a powerful key figure in the political administration of
his day. The imperial edict to erect the great statue of
Buddha at Todaiji Temple was issued in 743, immediately
following the smallpox epidemic. This was an attempt byEmperor Shoumu to entreat the power of Buddhism and thegreat Buddha to break free from these epidemics, famine,social unrest and political turmoil (3:34-36, 6:131-134).
Meanwhile, Emperor Shoumu issued orders through the
Department of State in 737 instructing every province to takepreventative measures against the disease. The treatment
measures were as follows: “Once smallpox symptoms appear,
do not drink cold water even though you may be so hot you
feel like you are burning. Once the scabs stop appearing, thefever will subside, but it may be complicated by diarrhea.
Wrap the belly and back in cloth to warm it; do not cool it.
Although the common people may have no beds, they should
not sleep directly on the ground. Take rice gruel, not fish or
fruit. Un-boiled water is strictly off limits. It is essential toeat, even if it is difficult. Take no pills or powdered
medicine.” These directions are extremely detailed andcomprehensive. It is interesting to note that medicine isregarded as ineffective (7:39-40). Patients had no choice but towait for a natural recovery.
Just like Europe and China had, Japan also suffered many
subsequent outbreaks. By the Edo Period, it was a disease
that everyone had encountered. It had a high mortality rate
among children; according to a detailed study by Dr. Keizo
Suda of the death registers held by temples in the Hida
district of Gifu, 68 of the 93 victims of smallpox in a villageof 2,733 people in 1804 were children aged 1-5 years (8).
Jenner’s cow pox vaccine made it as far as Kwangtung in
Qing dynasty of China by 1805, but took a little longer toreach Japan. Leading doctors in Japan learnt what

vaccinations were by reading the Chinese books of the day.
A smallpox outbreak in 1847 prompted two programs tointroduce cow pox vaccinations to the domains of Echizen
and Saga. Although the Echizen program did not succeed inbeing implemented, in 1849 Saga acquired some active cow
pox from Batavia (Jakarta) with the help of O. G. J. Mohnike,a Dutch doctor in Nagasaki. One of the Saga Domain doctors,
Sōken Narabayashi, promoted the vaccine after successfully
testing it on his own children, thus marking the beginning ofvaccination in Japan (9).
Time went on, and in 1958 the World Health Organization(WHO) embarked on a campaign to eradicate the disease
through a world-wide smallpox eradication program,
deploying a surveillance (Note 1) and containment strategy ofadministering the vaccine in the vicinity of infected people.
As a result, smallpox dramatically decreased and was
declared eradicated in May 1980 by the WHO. Since then,the smallpox virus is believed to no longer exist naturally.
This is the first infectious disease to be successfully
eradicated by humans.
Tuberculosis
Tuberculosis is caused by the human-type tubercle
bacillus Mycobacterium tuberculosis, an acid-fast bacterium.
It causes inflammation of the lungs and other internal organs,which eventually fester, destroying the tissue. (Humans canalso be infected by a bovine tubercle bacillus, which is also
highly pathogenic; in Japan this is kept under control by the
Act on Bovine Tuberculosis Control and there have been noreports of bovine tuberculosis in humans.)
The existence of tuberculosis as a disease has been known
since ancient times. The oldest and most well-known proofof this is an Egyptian painting depicting characteristic thedeformation of spinal tuberculosis (Pott’s disease). A female
skeleton with spinal tuberculosis has been discovered at the
predynastic site of Adaima (6500-5100 BCE). Studies onmummies have also confirmed that tuberculosis was acommon disease in Egypt around 3700-1000 BCE. X-rays
have also revealed tuberculosis lesions on a female mummy
from the Mawangdui site in China, dated around the second
century BCE (2:69-73, 11). According to a study by Aoki, humantuberculosis probably adapted from the bovine tuberculosis
bacillus found in cows, pigs, sheep and goats on entering thehuman body through the consumption of meat or the
consumption of milk, which can very commonly containhigh amounts of the tuberculosis bacillus (10). Based on theabove, the tuberculosis bacillus is thought to have first
affected humans around 7000 years BP.
In Japan, people have suffered from pulmonary
tuberculosis since ancient times. The earliest evidence oftuberculosis in Japan is two human bones with signs ofadvanced spinal tuberculosis, found among 5000 humanbones uncovered at the Yayoi-period Aoya-Kamijichi site in
Tottori. While numerous human skeletons have beenunearthed from Jōmon period sites, no evidence ofSystematized Survey on the History of Drug Discovery with Technical Development

9

tuberculosis has been found among them, indicating that thedisease was brought to Japan by migrants from the Asian
continent. It was prevalent among the nobility in the Heian
Period, even mentioned in The Pillow Book, but theconditions of that time were not conducive to chronic
infection and dramatic increases in patient numbers.
Repeated minor outbreaks occurred and died away up to andinto the Edo Period (10, 11). Dramatic increases in patientnumbers started occurring in the Meiji Period, when the
population became more concentrated in urban areas and thepromotion of industry led to harsher working conditions.
Influenza
Three types of influenza affect humans: A, B and C, allbelonging to the Orthomyxoviridae family of negative-sense
single-stranded RNA viruses. The virus infects airway
epithelial cells and develops into a respiratory illness. It has ahigh mortality rate, with complications including pneumonia,
brain inflammation and heart failure.
Outbreaks of diseases presumed to be influenza have been
observed since the Greek and Roman Empires. Hippocrates
famously described an incident strongly suggestive of
influenza in 412 BCE: “one day, many villagers suddenly
contracted a fever with trembling and much coughing. This
mysterious illness spread quickly throughout the village,causing fear among the villagers, but it went as quickly as it
had come” (12).
The influenza virus was brought to Japan from thecontinent. Dr. Shizu Sakai writes in Yamai ga Kataru
Nihonshi, “we see that influenza had already spread to Japanin 862 from an account in Sandai Jitsuroku that ‘many
people suffered from violent coughing and a great number
died’” (3:111-120). Outbreaks of violent coughing are recorded
in history books from the Heian Period (1150 CE) and theKamakura Period (1233 CE). Envoys from overseas are
known to have come to Japan in both of those years; it isvery likely that they brought viruses with them fromoverseas.
In the Edo Period, there were no more outbreaks after the1614 outbreak until 1730. This is presumed to be because
Japan had entered a period of national isolation and had nocontact with other countries. Even today, treatment for
influenza includes health management, vaccination andantiviral drugs at the early stages of infection; there are no
drugs that will completely get rid of the virus after onset.
Spanish influenza caused a worldwide pandemic in
1918-1919, claiming over 20 million lives. Five hundred
thousand people died in the United States; according to
Influenza, a report published in 1922 by the Central Sanitary
Bureau of the Japanese Ministry of Home Affairs, 385,000
Japanese lost their lives (the population at the time was 56.7
million) (14). Other worldwide influenza pandemics haveoccurred since then as well. The influenza virus mutates very
easily and can mutate in other mammals as well, making it
one of the most vigilance-requiring pathogens known today.

10

Measles
Like smallpox and influenza, measles is caused by a virus.
The measles virus is a single-stranded RNA virus in the
Morbillivirus genus of the Paramyxovirinae subfamily. As it
is genetically similar to the bovine virus rinderpest, there is atheory that it evolved from this into a human virus around
10,000 years BP with the domestication of cattle. It is also
assumed that its earliest endemic area was somewhere in the
Middle East around 3000 years BP. It is highly contagious;
once it spreads to a region, most of the people in that area
will be infected. Once infected, patients experience a tinglingor stinging sensation in the throat or on the skin; thissensation is termed hashikai in the Kansai dialect. Patientsthen experience fever accompanied by conjunctivitis andcoughing, later followed by high fever and rash all over the
body. Like smallpox, after a person has contracted it once
they are then immune to it for life; however, there has neverbeen a way to cure it and many people have lost their lives orgone blind because of it (15).
In Japan, the Fusō Ryakuki records an outbreak in 998 CE,
at the height of power of Fujiwara no Michinaga. Anothermajor outbreak is recorded in 1256 during the Kamakura
Period, but at that time there was nothing that could be done
except pray to the gods and change the name of the era.
There are 13 known instances of measles outbreaks during
the Edo Period, coming in 10-20 year cycles; it is said that no
man or woman of any age was unaffected. It is presumed thatmany deaths occurred as a result of complications from otherinfections as well as the measles itself (3:192-202).
As was the case with smallpox, humanity was saved frommeasles by a vaccine. The development of inactivatedvaccines and avirulent vaccines has now reduced the numberof measles patients. The WHO is currently implementing ameasles eradication program targeting measles as the next
disease to eliminate after smallpox.
Syphilis
Syphilis flared into virulence in Europe at the end of the
15th century, taking countless lives since with a vehemencethat has not been seen since among venereal diseases.
Thought to have been brought back with Columbus from
Haiti, two thirds of the officers and men are said to havebeen infected by syphilis as it spread throughout Europe bymeans of the women who accompanied the soldiers.
Syphilis is a chronic infectious disease caused by infection
from the spirochaete bacterium Treponema pallidum. It has
an incubation period of around three months, followed by asecondary stage of headache, fever and tiredness,accompanied by the outbreak of syphilitic lesions all over the
body and arthritis. Eventually, the disease enters a latentstage, leaving only a swelling of the lymph gland. Patients
may enter a tertiary stage three years after infection,affecting all of the organs, causing tissue damage and thecollapse of the nose or other parts of the body. A fourth stage
can occur after ten years, causing damage to the brain andspinal cord, leading to paralytic dementia and loss ofcoordination of movement.

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In 1493, while Columbus was reporting the success of his

and distributed in Doshomachi, the wholesale drug district ofexpedition to Queen Isabella in Barcelona, syphilis was

Osaka (13). The instructions for this pill were to “learn disease

spreading throughout the city and then across all of Europe atprevention, use fumigation when a disease comes and finallyan incredible speed. Syphilis made its appearance in the

crush and take”. An analysis of pills still in existence

Kansai region of Japan in 1512, transmitted either from Ming

revealed that they contained arsenic; they would have

China or by Japanese pirates, and soon spread throughout theprobably had no effect against cholera.
In 1858, the US frigate Mississippi arrived in Nagasaki
from China, bringing cholera with it. Booklets
recommending the treatment of cholera with quinine andopium, then known to be specific medicines for malaria,
were translated into Japanese, printed in Nagasaki anddistributed throughout the country. However, althoughquinine performed spectacularly in preventing infections,from a scientific standpoint, it was not a cure-all for all
infectious diseases. Cholera broke out again in 1877, startingin Yokohama and Nagasaki (17).
On contracting infectious diseases, people in ancient andmedieval times would have had no recourse other thansymptomatic treatment, as the existing crude drugs wereunable to eliminate the pathogenic microbes causing thedisease. Humanity started winning this battle in modern
times, as economic development led to environmental
hygiene and developments in nutrition led to sufficientnourishment to allow the body to build resistance, as well as
the emergence of antibacterial drugs and antibiotics to kill
the pathogens.
From ancient times to modern, infectious diseases havebeen our greatest enemy, in Japan and Europe alike. Being
an isolated island nation has meant that epidemics prevalentin Europe and across the Eurasian continent have not spreadto Japan immediately; however, these eventually did spreadto Japan, borne by bacteria and viruses aboard trading
vessels travelling to and from the continent. Smallpox,
measles, influenza and other viral diseases caused repeatedpandemics from ancient times to the Edo Period with no
crude drugs offering any cure. For gastrointestinal diseases(typhoid fever, dysentery), the main medications were
stomachic or intestinal Chinese remedies or Chinese
remedies with antipyretic or analgesic effects.
While nutrition, hygiene and specific medicines played amajor role in safeguarding against infectious diseases, there
were no adequate countermeasures in Japan from ancient toearly modern times. Edward Sylvester Morse, who
discovered the Ōmori shell midden, arrived in Japan in 1887
and recorded his impressions in Japan Day by Day.
“Somewhat astonished at learning that the death-rate ofTokyo was lower than that of Boston, I made some inquiries
about health matters. I learned that dysentery and cholera
infantum are never known here; some fevers due to malaria
occur, but are not common; rheumatic troubles show
themselves among foreigners after several years’ residence.
But those diseases which at home are attributed to bad
drainage, imperfect closets, and the like seem to be unknown
or rare, and this freedom from such complaints is probably

whole country. This took place before the Portuguese arrived
at Tanegashima in 1543.
Mercury patches and fumigation, long used in Europe totreat scabies, were used as treatment, but many people diedof mercury poisoning from the treatment process (16:100-123).
In the Edo Period, sarsaparilla was used as a specific crudedrug, but it would have had little effect, as discussed
previously.
DysenteryAn orally transmitted infection caused by the Shigellabacillus, named after Kiyoshi Shiga, who discovered it in
1898. Infection by the Shigella bacillus damages the tissuesof the intestinal epithelium; infected macrophages andinflammatory cytokines released by intestinal epithelium
cells cause hemorrhagic diarrhea and fever.
Shizu Sakai writes that “from an account in Sandai
Jitsuroku, it is thought that dysentery spread to Japan fromthe Chinese continent at an early stage. There are
surprisingly few records of dysentery” (3). Dysentery seems
to have spread when the body was weakened by the spread ofother diseases rather on its own. Fujiwara no Sanesuke,
author of Shōyūki, used expensive myrobalan plums to treat
dysentery. This crude drug from India was hung from poles
with string, “more to appease the evil spirits than as a
medicine” (2:187-191). Most people would have had no choice
but to wait for the worst to be over.
CholeraCholera is an orally transmitted infection caused by thebacteria Vibrio cholerae. It takes hold and multiplies in thelower small intestine; cholera toxins produced at the site of
infection invade other cells, causing severe diarrhea andvomiting, which leads to dehydration.
Although cholera had existed in Asia since ancient times,
it was not until the 19th century that there were any signs of aworldwide pandemic. Cholera is thought to be endemic to
the lower reaches of the Ganges River, a region ranging from
Bengal in India to Bangladesh. The oldest record of cholera
dates from around 300 BCE. While there are records of
epidemics thought to be cholera in 7th century China and 17th
century Java, there were no worldwide pandemics until 1817.
The first outbreak of cholera in Japan was in 1822. Koan no
Kusuribako (Medicine Box of Koan) notes that a pill madefrom tiger skulls, believed to kill evil spirits, was developed

Systematized Survey on the History of Drug Discovery with Technical Development

11due to the fact that all excrementitious matter is carried outof the city by men who utilize it for their farms andrice-fields. With us this sewage is allowed to flow into ourcoves and harbors, polluting the water and killing all aquatic
life; and the stenches arising from the decomposition andfilth are swept over the community to the misery of all”.
Hygiene conditions may have been surprisingly good in the
Edo Period (18).

[17] The Pharmaceutical Society of Japan (ed.): Nihon
Yakugakukai Hyakunenshi (100-year History of thePharmaceutical Society of Japan). 7 (1980).
[18] Morse E., Ishikawa K. (trans.): Nihon Sono Hi Sono Hi(Japan Day by Day). Kodansha Gakujutsu Bunko(2013).

2.2 Dawn of Modern Science and Medicine(Advances in Organic Synthetic Chemistry

Note 1: Surveillance – Survey monitoring. Here it refers toinvestigating trends in infectious diseases.

References[1] Cloudsley-Thompson J.L., Konishi M. (trans.): Rekishi
wo Kaeta Konchū-tachi (Insects and History).
Shisakusha (1990).
[2] Kato S.: Jinrui to Kansenshō no Rekishi (History of
Mankind and Infectious Diseases). Maruzen Publishing
32-36 (2013).
[3] Sakai S.: Yamai ga Kataru Nihonshi (The History ofJapan as seen from Diseases). Kodansha (2002).
[4] Kato S.: Modern Media “Jinrui to Kansen-shō to no
Tatakai (Mankind's Battle with Infectious Diseases)”. 55(11): 283 (2009).
[5] Ishizaka T.: Kusuri no Rekishi (History of Medicine).
Nippon Hyoron Sha 131-134 (1979).
[6] Sato M.: Nihon no Jidai-shi 4 “Ritsuryō Kokka to
Tenpyō Bunka” (History of Japan 4: Nations under the
Ritsuryo Codes and Tenpyo Culture). Yoshikawa
Kobunkan 143 (2002).
[7] Okazaki K.: Kusuri no Rekishi (History of Medicine).
Kodansha 39-40 (1976).
[8] Suda K.: Hida O Jiin Kako-chō no Kenkyū (Study of the
Death Records in Hida O Temple). Seijinkai Suda
Hospital (1987).
[9] Shia T.: Teki Juku no Nazo (Mystery of Cram Schools).
Osaka University Press 45-52 (2005).
[10] Aoki M.: Kekkaku no Rekishi (History of Tuberculosis).
Kodansha (2003).
[11] Aoki J.: Kekkaku no Shakai-shi (Social History ofTuberculosis). Ochanomizu Shobo (2004).
[12] Murphy B.R. and Webster R.G.: Orthomyxoviruses in
Field’s Virology. Third Edition edited by Fields B. N. et
al. Lippinncott-Raven Publishers 1397 (1996).
[13] Yoneda K.: Kōan no Kusuribako (Medicine Box ofKoan). Osaka University Press 111-113 (2001).
[14] Ikeda K., Fujitani K., Nadaoka Y., Kamiya N.,
Hirokado M., and Yanagawa Y.: Precise Analysis of the
Spanish Influenza in Japan. Tokyo Metropolitan
Institute of Public Health Annual Report 56: 369-374(2005).
[15] Kato S.: Modern Media “Jinrui to Kansen-shō to no
Tatakai (Mankind's Battle with Infectious Diseases)”. 56(7): 159-171 (2010).
[16] Tatsukawa S.: Byōki no Shakai-shi (Social History of
Diseases). Iwanami Gendai Bunko (2007).

12

and Isolating and Identifying Ingredients)
2.2.1.

Age of Isolating Active Ingredients in Crude
Drugs (1800 CE)(Advances in Organic Synthetic Chemistry and Isolating
and Identifying Ingredients)
Breaking away from the medieval and into the modern
started with the anthropocentrism movement, which had
begun during the Renaissance in 15th century Europe. By themid-16th century, modern natural science had begun todevelop through scientific methodologies that emphasizedmathematics and empirical results, distinct fromconventional philosophy and theology. The field of medicine
also began to undergo significant changes, influenced bymodern science.
Although some of the crude drugs derived from natural
products used for medication since ancient times
demonstrated some strong effects, many of them were usedin the form of mixture extracts. Medieval doctors had anumber of different drugs and would prescribe them incomplicated formulations. There are records from theRenaissance period recording as many as 60 types of crude
drugs being prepared in a solemn ceremony. As medical
science progressed, doctors gradually began to break awayfrom these “shotgun” drug preparations. Modern
pharmacopeia started being compiled from the 16th century
onwards in many countries and a number ofsuperstition-based substances were done away with (1).
In the 19th century, the advancement of modern science
made it possible to isolate and identify the ingredients of
conventional crude drugs, determine their structure andproduce synthetic substances using organic chemistry.
Pharmacists in Europe in the early decades of the 19th
century isolated morphine, strychnine, quinine and otherorganic compounds from medicinal plants, thus paving news
roads of development in organic chemistry. Justus Freiherr
von Liebig followed on from the efforts of these pharmacists
and further developed organic chemistry, as well as training
up a number of other notable organic chemists.
Many of the alkaloids isolated from crude drugs hadstrong pharmacological activity and created issues when
directly administered to patients; however, quite a few ofthem are still being used in clinical trials with different
dosage regimens (discussed below: see Table 2.6). Thesealkaloids were also used as a pharmacological research tool
to investigate the action mechanisms of drugs and have madea significant contribution to the development of modern

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchpharmacology.
The following sections discuss “substances discovered
and isolated from crude drugs”.

antidiarrheic effect of opium was indispensable for stopping
the strong diarrhea caused by dysentery, which was very
infectious. Even today, morphine is used for an antitussiveMorphine
Throughout history the world over, opium has taken
center stage as an unrivalled drug for alleviating pain andinducing sleep. It appears on Sumerian clay tablets, ancient
Egyptian manuscripts, Greek epic poetry and Dioscorides’
pharmacopoeia.
Once a poppy has bloomed, its petals fall off within 10-20

and to treat diarrhea, although it remains essential in medical
treatment for its role as an analgesic (2, 3, 4).
Opium contains more than 20 types of alkaloids. Codeine(content in opium 0.4-1%) was isolated in 1832, while
papaverine (content in opium 0.4-0.8%) was isolated in 1848.
Codeine has one fourth of the analgesic effect of morphineand is still used clinically today as an antitussive, a sedative,

days. Scratching the skin of the immature seed pod causes aan analgesic and a symptomatic treatment for severe diarrhea.

milky substance to ooze out (see Figure 2.1). This oxidizes

Modern pharmacology has confirmed that papaverine has ainto a dark clay-like substance known as raw opium.

phosphodiesterase (Note 2) inhibiting effect; it is still used

Cultivation of opium poppies started in the region around

today as an anticonvulsant. Narcotine (4-7%) was isolated byTurkey and was brought from there to Mesopotamia. It later

Jean-François Derosne; used today as a central antitussive, it

spread to the surrounding regions as a result of Alexander’swas renamed noscapine as it has no narcotic action (2, 4).

eastern expedition and the spread of Islam. In Japan,
cultivation of opium poppies started in Aomori during the
Edo Period.
Opium’s ability to take away the effects of pain has been
well known since ancient times, although the reason for its
efficacy long remained a mystery, despite the efforts ofcountless physicians. As modern science began attempting toclarify the medicinal ingredients in crude drugs from the

Scraped poppy seed pod

Renaissance onwards, it would seem that opium was the
Poppy flowers

natural choice for a starting point.
However, although opium was a crude drug that had
demonstrated outstanding efficacy since humankind
discovered, it was difficult to deal with due to being highly
addictive, as historically evidenced by the Opium Wars.

Morphine

Opium is a compound of several alkaloids, with the main
ingredient being morphine, with a molecular weight of 285,
successfully isolated by German pharmacist Friedrich
Wilhelm Adam Sertürner in 1817 (Note 1). However, morphine
has a very complex, three-dimensional structure; defining its
chemical composition and structural arrangement meant
waiting for advances in organic chemical technology. Prof.
Robert Robinson of the University of Manchester presented astructure the same as the one we know today in 1925,

Since ancient times, poppies have been cultivated all around the world. They have long been
known for their strong pharmaceutical effects, including anesthesia and analgesia, and theiraddictive properties. Morphine, a key ingredient in the opium harvested from the poppy seed
pod, was isolated by Friedrich Sertürner in 1803. Pictures of poppies have been found inJapanese books on medicinal plants.

Top photos:

Poppy flowers and seed pod: The Tokyo Metropolitan Medicinal
Plants Garden (Kodaira) has a poppy garden enclosed within adouble fence. Photograph courtesy of Prof. Yoshihito Okada.
Bottom photo: From Honzō Zufu (Vol. 23). Image supplied by the Tokyo
National Museum.

Fig. 2.1

actually 120 years after Sertürner first isolated morphine. In

Morphine Isolated from Opium Harvested
from Poppies.

1947, Robinson received the Nobel Prize in Chemistry for
his alkaloid research. Although today there is a branch of
medicine dedicated to pain and active research is being
carried on analgesics, very few drugs have been developedthat are as effective as morphine at alleviating pain.
The side effects of morphine include nausea, vomiting andsevere constipation due to decreased gastrointestinal
peristaltic movement (when using morphine for medical
treatment, other drugs must be taken concomitantly tocontrol these side effects). Arabian doctors in the Saracen
Empire used opium to treat dysentery; the strong

Acetylcholine-Related Alkaloids
Acetylcholine plays a very important role in the body as aneurotransmitter in a number of different nervous systems,
including the central nerves, peripheral nerves, autonomic
nerves and somatic nerves. The discovery of certain alkaloids,
discussed below, made a significant contribution to rapid
advancements in neuropharmacology in relation toacetylcholine.
The rhizomes and roots of Japanese belladonna Scopolia
japonica, the leaves of henbane Hyoscyamus niger, theleaves of devil’s snare Datura tatula and the roots of deadly

Systematized Survey on the History of Drug Discovery with Technical Development

13

nightshade Atropa belladonna, all members of theHenbane flowers

Belladonna flower

nightshade family Solanaceae, have long been used all
around the world as crude analgesics, antispasmodics,
antitussives and anesthetics (Note 3). The ancient Sumerians are
known to have used poppies and henbane for pain relief;
first-century Greek physician Pedanius Dioscorides also
recorded their anesthetic effect. In Japan, surgeon Seishū
Hanaoka is known for being among the first in the world toperform surgical procedures using general anesthetics. In

Deadly nightshade Atropa belladonna has a
habitat extending from Europe to West Asia
Mainly the root is used
Photographs courtesy of Prof. Yoshihito
Okada of the Meiji Pharmaceutical
University Medicinal Plant Garden

Henbane Hyoscyamus niger grows
from Europe to Asia. The leaves areused for crude drugs Not native toJapan

1804, Hanaoka performed a partial mastectomy for a breast
cancer patient under general anesthetic using a herbal

Scopolamine and hyoscyamine structures shown below

mixture containing six types of herbs, mainly devil’s
trumpets (Datura) and wolf’s bane (Aconitum), having
confirmed the general anesthetic effect of this mixture
through trial and error.

Hyoscyamine

Scopolamine

In the medieval Western world, belladonna was also
widely used by women as a beauty treatment, as it would
dilate the pupils. It is one of the so-called mydriatic drugs.
Into the modern era, pharmacists extracted and identified
various ingredients from this family of plants with its

Fig. 2.2. Active Substances Found in Plants in the
Family Solanaceae with Acetylcholine-Like
Effects on Nerves (1).

extremely diverse range of effects. These alkaloids include
atropine, ℓ-hyoscyamine (atropine is a racemic mixture of (dand ℓ-) hyoscyamines) and scopolamine. Each of these has
their own strong antiacetylcholine effect and some of their

The crude drug Scopolia Rhizome is made from therhizomes and roots of Japanese belladonna Scopolia
japonica, henbane bell Scopolia carniolica or Korean
scopolia parviflora. These plants grow in Europe andAsia and are also known as the “mad eggplants” inJapanese.
Generally speaking, Japanese belladonna Scopolia
japonica is native to Japan

component ingredients are still used in medical treatment
today.
Japanese belladonna flower

Later, physostigmine and iso-physostigmine were isolated
from the calabar bean Physostigma venenosum in the

The crude drug Datura is made from theleaves of devil’s snare Datura tatula(native to the Americas; naturalized inJapan) and devil’s trumpet Datura
stramonium (native to the Caspian Sea
region).

Leguminosae family, while muscarine was isolated from thefly agaric Amanita muscaria and pilocarpine from the leavesof jarabondi Pilocarpus jaborandi. Each of these alkaloids
has an effect on acetylcholine neurotransmission and they

Devil’s snare flower

have played a pivotal role in the advancement of modern

Photographs courtesy of Prof. Yoshihito
Okada of the Meiji Pharmaceutical
University Medicinal Plant Garden

Atropine and hyoscyamine are extracted from Scopolia and Datura

pharmacology (discussed later).
Currently, the crude drug “Scopolia Rhizome” listed in theJapanese Pharmacopeia is described as containing not less

Atropine is a dℓ-mixture

than 0.29% total alkaloids (hyoscyamine, scopolamine), as
well as other related alkaloids, with Japanese belladonna
Hyoscyamine is an ℓ-isomer

Scopolia japonica as the plant of origin. Similarly,“Belladonna Root” is described as containing not less thanFig. 2.3. Active Substances Found in Plants in the

0.4% hyoscyamine, as well as several other alkaloids besides

Family Solanaceae with Acetylcholine-Likeatropine and scopolamine. The crude drug “Datura” isEffects on Nerves (2).

derived from devil’s snare Datura tatula and devil’s trumpet
Datura stramonium, used by Seishū Hanaoka; however, it isAtropine, Hyoscyamine and Scopolamine
Atropine was isolated from belladonna root in 1833 bydangerous and has been prohibited from private use.

German pharmacists Philipp Geiger and Ludwig Hesse.

Accordingly, it does not appear in the JapaneseModern science has shown it to have an antagonistic effectPharmacopeia (see Figures 2.2 and 2.3)

(2, 6, 7).

on the neurotransmitter acetylcholine in acetylcholine
receptors. This knowledge has sped up research on receptors

14

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchhave an inhibiting action on cholinesterase, a catabolic
enzyme of acetylcholine, they prolong the activity ofacetylcholine and thereby systemically enhance the action ofacetylcholine (Barger and Stedman: 1923). Consequently,
these could be used as antidotes to drugs that suppress
acetylcholine in the nerves. Neostigmine is also used as a
symptomatic treatment for myasthenia gravis.
Muscarine was first isolated from the fly agaric Amanita
muscaria in1869 by Oswald Schmiedeberg and Richard
Koppe. Its pharmacological action was found to be that of aparasympathomimetic agonist, binding to the acetylcholine
receptor in the membrane of the postganglionic nerve andmimicking the action of the neurotransmitter acetylcholine.
This receptor is a muscarinic acetylcholine receptor; thisalkaloid led to the discovery that there are two types ofacetylcholine receptors. The other acetylcholine receptor isthe “nicotinic acetylcholine receptor”, which is affected by
nicotine (see Figure 2.4).

and sympathetic nervous systems, thereby contributing
greatly to the development of modern pharmacology.
Atropine is a racemic mixture; hyoscyamine is its ℓ-isomer,
also isolated from belladonna by Geiger and Hesse in 1833.
Its structure was defined by Albert Ladenburg in 1879.
Ladenburg also isolated scopolamine from henbane leaf in
1881. It was found that these alkaloids suppress the action of
the parasympathetic nerve by acting against the “muscarinic
receptors” affected by the neurotransmitter acetylcholine (ananticholinergic action), thereby suppressing gastrointestinal
motility and also increasing the heart rate.
Atropine is used today as an antispasmodic drug with an
anticholinergic action, while scopolamine is currently thestrongest anticholinergic drug used for motion sickness (4, 7).
Physostigmine, Neostigmine, Pilocarpine andMuscarine
Physostigmine was isolated from the calabar bean in 1864
by Julius Jobst and Oswald Hesse. It was later clarified thatsince physostigmine and neostigmine (discoverer unknown)

Ach:
Acetylcholine

Acetyl CoA
Ach synthase

Action potential

Choline

CholineAcetylcholine

Acetic acid+

Ca influx
Choline reuptake

Acetylcholine
Ach release

Acetic acidAch esterase
Synaptosomes

CholineAch receptors

 Nerve endings join to “other neurons” and “muscle cells”; these junctions are called synapses. There is a gap at the join.
 Within the nerve cell, information is transmitted by electric stimulation; at the synapse, information is transmitted by the release ofchemical substances. Acetylcholine (Ach) and noradrenaline are stimulation transmitters secreted into the synapses.
 Cells transmitting the information are called “presynaptic cells”, while those receiving the information are called “postsynaptic cells”.
Muscle cells and the like are postsynaptic cells.

1)
2)
3)
4)
5)
6)

Ach is synthesized within neurons from acetyl CoA and choline.
The synthesized Ach is stored within synaptosomes.
Ca ions influx by electric stimulation and Ach is released outside the neuron.
The released Ach moves to the Ach receptors and stimulation is transmitted to the postsynaptic cell.
Ach released into the intercellular gap is broken down by the catabolic enzyme cholinesterase, forming choline and acetic acid.
Choline reuptake mechanism operates to recycle it back to the presynaptic cell.

Alkaloids extracted from crude drugs served as tools to clarify the action of the Ach system.
 In 4), atropine acts against Ach with an Ach inhibiting action. Scopolamine acts the same way.
 In 4), pilocarpine demonstrates an Ach-like action (nonselective agonist).
 In 4), muscarine demonstrates a selective Ach-like action on the muscarinic acetylcholine receptors (selective agonist).
 Physostigmine and neostigmine inhibit Ach esterase in 5). As a result, the Ach activity is prolonged.

Fig. 2.4. Acetylcholine (Ach) Metabolism at Acetylcholinergic Nerve Endings.

Systematized Survey on the History of Drug Discovery with Technical Development

15

Pilocarpine was discovered in the leaves of jarabondi
Pilocarpus jaborandi in the Rutaceae family by Ernest

Strophanthin

Hardy in 1874. It was found to act as a nonselective
muscarinic agonist.

among native inhabitants of Africa. Strophanthin was

A compound used for poisoned arrows since ancient times
extracted from the seeds of plants in the Apocynaceae andBuddlejaceae families by Pierre-Joseph Pelletier et al. in

CurareWhen Europeans began travelling to South America in the1818. Strophanthin contains many impurities; in 1888,

16th century, reports came back of the native inhabitants ofSouth America using poisoned arrows. This poison, withcymarin and other glycosides (Note 4) (16). While it has alethal effects ranging from motor paralysis to dyspnea, was
known as curare and drew much attention in Europe. In 1844,

François Arnaud found it to contain ouabain (g-strophanthin),cardiotonic effect similar to foxglove (Note 5), it is highly toxic,
with side effects including nausea, vomiting and cardiac

Claude Bernard reported that curare blocked stimuli from thebrain, causing the loss of normal muscle control.

arrhythmia (8:71-75).

Meanwhile, it was found that the native inhabitants useddifferent formulations in different locations, with

Cocainecombinations of several dozen different ingredients fromvarious different plants. Analysis of these ingredients took

have been chewing coca leaves around 3000 BCE to increasesome time; they were not fully identified until 1935 in apaper by Harold King (8:282-289).

coping with the thin air in the Andean highlands. Coca is a

Several substances have been isolated from curare. The
quaternary base (N-R+) structure of one of these substances,

ingredients in coca leaves proved difficult to analyze;

tubocurarine, has been the subject of much attention; it has
been developed into surgical muscle relaxants

Gaedcke isolated cocaine from the coca leaf in 1855, further

decamethonium and suxamethonium, as well as the
hypotensive drug hexamethonium (no longer used).

The people of the ancient Inca Empire are believed totheir heart rate and quicken their breathing as a means ofpalatable drug that quickly creates physical dependency. The
however, reports indicate that “German chemist Friedrichvalidated in 1859 by German organic chemist Albert
Niemann” (8:21-22). Although cocaine abuse is now an issue

Tubocurarine has been found to have an antagonistic effecton acetylcholine in the peripheral nerves and a skeletal

faced by more than three million Americans, it is still usedmuscle relaxant effect in the limbs that paralyzes the motor
nerves (10).

Schroff and Louis-Gustave Demarle in 1862.

clinically for its local anesthetic effect, discovered by Carl

Ergot
Foxglove
Foxglove Digitalis purpurea is a perennial plant native toEurope, known to be poisonous since ancient times. In 1775,

people who ate moldy rye bread with ergot fungus Claviceps

William Withering found from folklore prescriptions thatfoxglove leaves have a diuretic effect. French chemist

circulation, leading to gangrene. An Assyrian clay tablet

Claude-Adolphe Nativelle isolated and identified digitoxin in
1869.

the ears of grains”. This mold acts on the central nervous

Foxglove formulations were complexes of several cardiac
glycosides and were used as specific medicines for heart

In times of food shortage in Europe, it was found that
purpurea growing on it would experience restricted bloodfrom 600 BCE records that “there are poisonous nodules on
system, causing confusion, drowsiness and convulsions.
However, around 2400 BP it was also found that when taken

failure due to their powerful cardiotonic effects. Althoughseveral chemical compounds were isolated, many of themin appropriate measures, this moldy bread could work to

had a narrow safety margin between intoxicating dose andeffective dose. Simple substances digitoxin and deslanoside

midwives to assist delivery.

have relatively wider safety margins and are still used today
as cardiotonics (4, 5).

diverse effects. Ergotoxine, ergotamine and ergotaminine

lower the uterus of a pregnant woman and it was used by
It was not easy to isolate the substances causing thesewere refined and isolated in 1906, although continued efforts
were made to isolate the many other substances contained.
Ergotoxine is made up of multiple substances and has apowerful vasoconstrictive effect. Ergonovine was isolated in1935 and was found to have a uterine smooth muscle
contraction effect.

16

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchLysergic acid diethylamide (LSD), a derivative from thisfrom a lot of pain. While a gentler derivative,

fungus, is similar to mescaline derived from American cacti.

dl-methylephedrine hydrochloride, is currently used as a

Rather than being a drug for the uterus or for migraines, itbronchodilator in prescription medicine, ephedrine itself is

acts on the central nervous system and has also become astill used as an over-the-counter cold remedy (2, 4).

social issue, as it causes hallucinations(8:92-108). Its

pharmacological effects include acting as an agonist of theserotonin, noradrenaline and dopaminergic neurons

(10)

.

QuinineQuinine kills malaria-causing protozoa by obstructing
polymerization and has saved countless lives. It is still used

Salicylic Acid

as a backup medication for Plasmodium infections that have

The analgesic and antipyretic effects of willow are widely
known around the world. Records exist among Hippocrates’

become immune to other drugs.
Cinchona plants are native to the South American Andes,

works, as well as in Sumerian, Assyrian and Egyptian

where the native inhabitants used the bark as an antipyretic

writings. Native Americans also used various willow trees

rather than to treat malaria. Although malaria has existed infor their analgesic and antipyretic effects. Even the Chinese

Europe since ancient times, it did not originally exist in theand Japanese knew of the use of “willow sticks for

Americas; it is presumed to have spread to the Americas withtoothache”.

the Europeans. The effects of cinchona bark in treating

In Europe, the medicinal use of willow as a crude

malaria were later discovered by chance; it started being

antipyretic was forgotten through disuse, despite the demand

imported to Europe in 1640 (8).

for willow increasing in the medieval period. It was not until

Portuguese doctor Bernardo Gomes isolated crystals fromearly modern times that the antipyretic effect of willow wasquinine in 1811, naming the substance cinchonine. In 1820,

rediscovered by Edmund Stone, in 1793.

pharmacist Pierre-Joseph Pelletier et al. found that Gomes’

Later, in 1830, French pharmacist Henri Leroux isolated

crystals were made up of quinine and cinchonine; by 1908

the antipyretic ingredient in willow and named it salicin.

they had isolated the quinine and determined its chemical

Salicylic acid is a substance isolated from salicin. Salicylic

structure. Total synthesis of it was achieved in 1944 byacid was used on patients suffering from rheumatoid arthritis.

Robert Burns Woodward, who was awarded the Nobel Prize

In 1897, Felix Hoffmann of German company Bayerin Chemistry in 1965 for his achievements in chemosynthesis,

acetylated salicylic acid to organically synthesize

including success with strychnine, reserpine and colchicine.

acetylsalicylic acid. Also known as aspirin, this drug has
Reserpine

made the most significant contribution to humankind inhistory(9).

Reserpine is a crude-drug-derived compound that has

Salicylic acid itself has a skin collagen softening effect, as

made a significant impact on modern pharmacology. It is

well as suppressing on Trichophyton fungi, which cause

extracted from Indian snakeroot Rauwolfia serpentina in theathlete’s foot. It is currently used in ointment, liquid or

Apocynaceae family, used as a crude drug in the Indian

medicated bandage form to treat psoriasis and keratosis, as

region, although it was not until 1952 that its ingredientswell as warts, calluses, corns and athlete’s foot(2, 4).

were isolated by Johannes Muller and Emil Schlittler.
Having been used in India since ancient times as a treatment

Ephedrine

for psychosis, insomnia and confusion, attention was drawn

Bluestem joint fir Ephedra equisetina is a shrub in theto its powerful pharmacological effects and it became thegenus Ephedra that is used in Chinese medicine as a

subject of Western research, initially as an antipsychotic drug.

diaphoretic, antitussive and antipyretic. It has also had

Later, it was found that it not only had an inhibitory effect onvarious applications in Western medicine for its

mental stimulation, but also hypotensive and sedative effects

sympathomimetic effects. Its main ingredient, ephedrine, wasas well. Reserpine became a major pharmacological research

extracted and identified in 1885 by Nagayoshi Nagai, whotool in the 1950s; at one stage, it was widely used clinicallylater became the first president of the Pharmaceutical Society

as a hypotensive (4, 10).

of Japan. Dr. Nagai also successfully achieved a large-scale
synthesis method for it, which became widely used.
Ephedrine has a bronchodilator effect and was used until
recently to prevent asthma attacks, saving a lot of patients
Systematized Survey on the History of Drug Discovery with Technical Development

17

Contributions by Japanese Scientists
The late 19th century saw the beginning of Japan’s Meiji
Period and notable efforts made by Nagayoshi Nagai andother Japanese scientists. The new Meiji government
implemented policies to promote industry, while the country
as a whole was actively absorbing new culture from the West.
The government issued a directive steering the field of
medicine away from Chinese medicine and towards
incorporating a German-medicine-centered approach. YoungJapanese scientists and doctors also made active efforts tostudy overseas to gain a foundation in Western medicine,leading to many discoveries and inventions.
Meanwhile, back on Japanese soil, much energy was
being invested into isolating and analyzing the ingredients inJapan’s own crude drugs. Yasuhiko Asahina isolated andidentified the ingredients in the lacquer tree Toxicodendron
vernicifluum (1906), while Kōjirō Makoshi did the same foraconite Aconitum japonicum (1909). In 1909, Yoshizumi
Tahara extracted tetrodotoxin from the ovaries of pufferfish
in the Tetraodontidae family. Kyōsuke Tsuda et al. ofSankyo determined the chemical structure of tetrodotoxin in
1964. Heizaburō Kondō identified the ingredients in red
spider lily Lycoris radiata in 1927 (11). The isolation of these
active ingredients by Japanese researchers has contributed tothe advancement of pharmaceutical science andpharmacology.
Thiamine (Vitamin B1)During Japan’s Edo Period, there was an ailment known
as “Edo disease”, which started as a peripheral nervous
system disorder and led to circulatory failure, eventuallyleading to weakness in the lower limbs and ultimately deathfrom heart failure. This sickness was rare in agriculturalcommunities, but often broke out in urban districts such as
Edo and Kyoto; it is now known to be beriberi. At the end of
the 17th century, rice prices had stabilized and people wereregularly getting three meals a day. The citizens of Edo, who
had been eating unrefined brown rice and other grains,
started eating refined white rice with the bran removed.
While this pure white rice was a luxury, the people of the day
had no way of knowing that it would lead to vitamin B1
deficiency. The disease did not exist in Europe, but
continued to affect many Japanese soldiers even into the
Meiji Period, causing great concern to the Meiji government,
whose policies were to increase national prosperity andmilitary power.
According to military hygiene records kept by the Army
Ministry Medical Bureau in the First Sino-Japanese War, 1
in 3.85 hospitalized soldiers were suffering from beriberi.
This means that patients with beriberi accounted for between
one quarter and one third of all hospitalized soldiers,
including those suffering from war wounds. The
Russo-Japanese War followed, and beriberi recurred in asimilar manner. Casualty numbers rose to 210,000, with18

beriberi accounting for around half of this figure (15). Other
records indicate that beriberi accounted for as much as 11.24
times as many casualties as war wounds (13).
Dutch pharmacologist Christiaan Eijkman, who conducted
research in Java in 1888, reported that beriberi does not
strike people with unrefined brown rice in their diet.
However, Japanese research in this area fell far behind, with
the Japanese medical community and army persisting withtheories that it was caused by infection or poison. Later,
studies by naval physician Kanehiro Takaki and Kiyoshi
Shiga et al. found that beriberi was linked to diet rather thaninfection, while Jinnosuke Tsuzuki, returning from studyingin Europe, confirmed that rice bran contained a substancethat could prevent and treat beriberi (13).
In 1910, Umetarō Suzuki successfully isolated the active
ingredient from the beriberi preventing component in ricebran. He named this ingredient oryzanin in 1912.
Casimir Funk had isolated an active ingredient from ricebran in 1911 and named it a vitamin. This ingredient was
vitamin B1, which had earlier been isolated by Umetarō
Suzuki (14). However, it was Eijkman who received the Nobel
Prize in Physiology or Medicine in 1929 for his researchachievements on beriberi and vitamin B1.
In 1923, as many as 27,000 Japanese died from beriberi.
This figure dropped in later years as people came to realize
the importance of vitamin B1, although it was not until theemergence of a number of vitamin B1 formulations in the late
1950s that the figure dropped below 1000 (15). By 1959,
beriberi had an incidence rate of around 0.1%.
Adrenaline
Jōkichi Takamine and his assistant Keizō Uenaka began
extracting and studying adrenaline using discarded livestockorgans, successfully extracting a crystal in 1900. Like
acetylcholine, the discovery of adrenaline led to significant
developments in research on neurotransmitters and receptors
and laid the foundation for modern pharmacology.
Adrenaline itself was also used as a styptic in all kinds ofsurgical procedures and made a significant contribution todevelopments in medical and pharmaceutical science (seeSection 2.3.4 below for details).
From the 19th century into the 20th century and to thepresent day, “alkaloids isolated from crude drugs” have beenutilized, with their efficacy noted in the JapanesePharmacopeia. However, these have not been great in variety
or number and it is mainly new drugs formulated based on
the action mechanisms of these alkaloids that are used inclinical practice.
There are currently 219 crude drugs listed in the
Pharmacopeia. Table 2.1 lists the alkaloids isolated fromcrude drugs, while Table 2.2 shows the alkaloids derived
from crude drugs listed in the Pharmacopeia.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchTable 2.1 Alkaloids Isolated from Crude Drugs (Note 6)

Year discovered

Ingredient

Discovered by

Crude drug

1803

Morphine

Sertürner

Opium

1818

Strychnine

Pelletier and Caventou

Poison nut tree

1820

QuininePelletier and Caventou

Cinchona bark

1820

Colchicine

Pelletier and Caventou

Meadow saffron

1821

Caffeine

Runge

Coffee beans

1828

Nicotine

Posselt

Tobacco leaves

1832

CodeineRobiquet

Opium

1833

Atropine

Geiger and Hesse

Deadly nightshade

1833

Hyoscyamine

GeigerHenbane1842

Papaverine

Geiger

Opium

1855

CocaineGaedcke

Coca leaves

1864

Physostigmine

Jobst and Hesse

Calabar bean

1869

Muscarine

Schmiedeberg and Koppe

Fly agaric

1869

Digitoxin

Nativelle

Foxglove

1874

Pilocarpine

Hardy and Gerrard

Jaborandi

1881

Scopolamine

Ladenburg

Hyoscyamus niger, devil’s
trumpet1885

Ephedrine

Nagai

Bluestem joint fir

1909

Tetrodotoxin

TaharaPufferfish ovaries

Table 2.2 Alkaloids Derived from Crude Drugs Listed in the Japanese Pharmacopeia, 16th Edition

Crude drug of origin

Pharmaceutical compound extracted
from crude drug

Opium

Morphine hydrochloride

Narcotic analgesic

Codeine phosphate

Narcotic analgesic / antitussive / antidiarrheal

Cinchona

Efficacy / Effect (Pharmacopeia)

Noscapine hydrochloride

Non-narcotic antitussive

Papaverine hydrochloride

Visceral smooth muscle antispasmodic for
gastritis / biliary tract diseases

Quinine hydrochloride

Antimalarial drug

Quinidine hydrochloride

Antiarrhythmic

Coca

Cocaine hydrochloride

Local anesthetic

SaffronColchicine

Gout suppressantFoxglove

Digitoxin

Cardiotonic

Japanese lime flower

Santonin

Anthelmintic

Tea

Caffeine

Non-narcotic antitussive

Ergot

Ergotamine tartrate

Non-narcotic antitussive (hypertensive migraine)

Ergometrine maleate”

Ephedra herb

Ephedrine hydrochloride

Antitussive agent (bronchial asthma)

Digenea

Kainic acid

Anthelmintic

Jaborandi

Pilocarpine hydrochloride

Miotic glaucoma medication

Indian snakeroot

Reserpine

Hypertensive emergency (cerebral hemorrhagic
attack, etc.)

Scopolia rhizome

Atropine sulfate

Antispasmodic / mydriatic / poison antidote

Belladonna root

Scopolamine hydrobromide

Antiparkinsonian

Around 30 crude drug ingredients are listed in the Pharmacopeia as standalone pharmaceutical compounds.
Most of the pharmaceutical compounds listed here can be chemically synthesized; however, the majority of them are extracted andisolated to be used directly as pharmaceutical raw ingredients.
The crude drugs listed here are those mentioned in this paper.
References: Japanese Pharmacopeia, 16th Edition (text and annotations). Hirokawa-Shoten (2011).
Mikage M. & Kimura M.: Dentō Iyakugaku / Shōyakugaku (Traditional Medicine/Pharmacognosy). Nankodo (2013).

Systematized Survey on the History of Drug Discovery with Technical Development

19

Note 1: Date calculation error: Sertürner wrote a paper on the
discovery of morphine in 1817, but this paper was ignored inGermany, as two French pharmacists had already isolated theactive ingredient in opium. One of these pharmacists,
Charles Derosne, presented a paper the active ingredient in
1803; this was later found to be a narcotine mixture. The
other pharmacist, Armand Séguin, published a report on
trace crystals from opium in 1814, but these were low inpurity, while Sertürner’s crystals were superior in quality andquantity. According to Ishizaka, Sertürner reported not only
his isolating the crystals, but also his testing of morphine onlive subjects, including himself. Other reports state that
Sertürner first isolated a basic substance from opium in 1803,
while yet other reports state that he did so in 1805 (3:75,
8:314-322).
Note 2: Broadly speaking, an enzyme that hydrolyzes
phosphodiester bonds. More specifically, an enzyme that hydrolyzes
cyclic phosphodiester bonds.
Note 3: Plants in the nightshade family Solanaceae: Tomatoes,
eggplants and potatoes are members of the Solanum genus in the
Solanaceae family; devil’s snare is a member of the Datura genus in
the Solanaceae family; henbane is a member of the Hyoscyamus
genus in the Solanaceae family; deadly nightshade is a member ofthe Atropa genus in the Solanaceae family; Japanese belladonna is amember of the Scopolia genus in the Solanaceae family.
Japanese belladonna is also known as the “mad eggplant” inJapanese, as it can cause abnormal behavior if ingested.
Note 4: A molecule in which a sugar is bound to a non-sugarcompound within a plant substance.
Note 5: Recent studies indicate that it inhibits the Na+ pump in
cardiac muscle cells, thereby increasing the Na+ concentration in thecell. This results in an increase in the Ca2+ concentration in the cell,
ultimately strengthening the myocardial contractility.
Note 6: Different records indicate different discoverers and different
years of discovery, because it is sometimes difficult to determine
who discovered what and when.

References[1] Singer C. & Underwood E., Sakai S. & Fukase Y.
(trans.): Igaku no Rekishi (A Short History of Medicine)Vol. 3. 673-679 (1986).
[2] Kariyone T.: Saishin Shōyakugaku (Latest
Pharmacognosy). Hirokawa-Shoten (1965).
[3] Amano H.: Kusuri no Rekishi (History of Medicine).
Yakuji Nippo (2000).
[4] Richard Harvey: Illustrated Pharmacology, Lippincott
Series (2012).
[5] Mikage M. & Kimura M.: Dentō Iyakugaku /Shōyakugaku (Traditional Medicine/Pharmacognosy).
Nankodo (2009).
[6] The Pharmaceutical Society of Japan (ed.): Shitte okitai
Shōyaku 100 (Must-know 100 Herbal Medicines).
Tokyo Kagaku Dojin (2004).
[7] Japanese Pharmacopeia, 16th Edition. Hirokawa-Shoten

20(2011).
[8] Taylor N., Nanba T. & Nanba Y. (trans.): Sekai wo
Kaeta Yakuyō Shokubutsu (Plant Drugs that Changed
the World). Sogensha (1972).
[9] Cooper, K. E.: Fever and Antipyresis: The Role of the
Nervous System. Cambridge: Cambridge University
Press. Pp.100-105 (1995).
[10] Tanaka C. & Katō R. (eds.): New Yakurigaku (New
Pharmacology). Nankodo (2011).
[11] The Pharmaceutical Society of Japan (ed.): Nihon
Yakugakukai Hyakunenshi (100-year History of thePharmaceutical Society of Japan). (1980).
[12] Amano H.: Kusuri no Rekishi (History of Medicine).
Yakuji Nippo (2000).
[13] Kujime Y.: Rekishi no Shuyaku wa Mina Byōnin (TheProtagonists of History were All Sick). Shufunotomo(2013).
[14] Sankyō Hyakunen-shi (100-year History of Sankyo):Sankyo Kabushiki Kaisha 39-40 (2000).
[15] Okazaki K.: Kusuri no Rekishi (History of Medicine).
Kodansha 249-252 (1976).
[16] Walter A. Jacobs, Newell M. Bigelow.: Ouabain or
g-Strophanthin. Journal of Biological Chemistry 96:
647-658 (1932).

2.2.2.
Age of Discovering Pathogens
Around 50 years after active ingredients started being
isolated from crude drugs, a succession of infection-causing
pathogenic microbes started being discovered in what is now
bacteriology. Specific pathogens for at least 21 diseases werediscovered between 1879 and 1900. Table 2.3 shows themain pathogen discoveries.
Charles Louis Alphonse Laveran was awarded the Nobel
Prize in Physiology or Medicine for his research on diseases
caused by malaria protozoa in 1907. This was the second
time a Nobel Prize was awarded in relation tomalaria-causing protozoa, the first being Ronald Ross
(discussed previously). This indicates the level of worldwide
attention paid to malaria at the time. That same year, Karl
Joseph Eberth discovered the typhoid fever bacterium
Salmonella typhi. Robert Heinrich Hermann Kochdiscovered the tubercle bacterium Mycobacterium
tuberculosis in 1882 and the cholera bacterium Vibrio
cholerae the following year. In 1884, Arthur Nicolaierdiscovered the tetanus bacterium Clostridium tetani.
There were also some notable efforts by Japanese doctors
and scientists. Shibasaburō Kitasato, who had studied inGermany under Robert Koch, successfully cultivated a pureculture of tetanus bacterium Clostridium tetani in 1889,
together with Emil Adolf von Behring. They were also thefirst in the world to discover serotherapy, developing
antiserums for diphtheria and tetanus toxins. This
achievement resulted in the awarding of the first Nobel Prizein Physiology or Medicine in 1901, although it was only

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchawarded to Behring (discussed later). Another of Kitasato’s
achievements was his discovery of the plague bacillus
Yersinia pestis in 1894, having been sent by the Meiji
government to Hong Kong, which was under attack by thebubonic plague.
Doctor and microbiologist Kiyoshi Shiga, who studied
under Shibasaburō Kitasato, discovered the dysentery
bacillus Shigella (Note 1), which was named after him(discussed previously). In 1913, Hideyo Noguchi discovered
the syphilis spirochete Treponema pallidum by studying
brain specimens from patients who had suffered fromterminal neurosyphilis that had led to motor ataxia andarthropathy. Noguchi also achieved research results in snake
venom serology, proving that Peruvian wart and Oroya fever
are both symptoms of Carrion’s disease. However, several ofhis published pathogen-specific reports were later repudiated.
Table 2.3 Pathogen DiscoveriesYeardiscovered
1849
1873
1879
1880
1880
1882
1883
1883
1884
1884
1885
1886

PathogenDiscovered by

Bacillus anthracis
Mycobacterium leprae
Neisseria gonorrhoeae
Malaria plasmodium
Salmonella typhi
Mycobacterium
tuberculosis
Vibrio cholerae
Corynebacterium
diphtheriae
Clostridium tetani
Staphylococcus
Escherichia coli
Streptococcus
pneumoniae

Aloys Pollender
Gerhard Hansen
Albert NeisserCharles Laveran
Karl Eberth1894

Yersinia pestis

1897
1900

Shigella
Salmonella paratyphi

1905

Treponema pallidum

1906
1909

Bordetella pertussis
Salmonella typhi

Robert Koch
Robert Kochimmunology.
The idea of chemical treatment took hold in this era andformed the basis for modern drug discovery. Drugs to fightpathogens living in the human body would have been a very
easy field to get involved in.
Numerous alkaloids were discovered from the time of
Sertürner onwards and were used against all kinds ofdiseases. Many of these substances were too toxic to be usedon their own and were put to more practical use in new fieldsof study. The discipline of pharmacology developed as
researchers began to examine the detailed mechanisms ofaction as to why these drugs were effective.
Pharmacology initially developed from research on drugs
that act on the nervous system. This began with analyses on
the parasympathetic nerves using atropine, scopolamine andphysostigmine, which act on acetylcholine, and was followed
by studies on sympathetic nerves using adrenaline. However,it was not until after the Second World War that themolecular-level mechanisms of neurotransmission wereidentified.
In contrast to the isolation of ingredients from plant-based
crude drugs, endocrine hormones were being extracted fromanimal organs. Alongside neuropharmacology, studies on
endocrine hormones facilitated pathological analysis andcontributed to advances in pathophysiology andpharmacology.

Edwin Klebs
Arthur Nicolaier
Alexander Ogston
Theodor Escherich
Albert Fraenkel
Shibasaburō
Kitasato &Alexandre Yersin
Kiyoshi Shiga
Hugo Schottmüller
Fritz Schaudinn &Erich Hoffman
Jules Bordet
Charles Nicolle

Excerpts taken from the following materials and othersources(1) Singer C. & Underwood E., Sakai S. & Fukase Y.
(trans.): Igaku no Rekishi (A Short History of Medicine)Vol. 2. Asakura Publishing Co. 391 (1986).
(2) Ishizaka T.: Kusuri no Rekishi (History of Medicine).
Nippon Hyoron Sha 179 (1979).
Note 1: Kiyoshi Shiga reported his discovery in Japanese in theJapanese Journal of Bacteriology in 1897 and published a paper inGerman in 1898.

2.3 The Origin of Modern Pharmaceutical Drug
Discovery and Development
While alkaloids were isolated from crude drugs andpathogens identified, medical treatment had to start withmeans of dealing with the pathogenic bacteria. Following on
from Edward Jenner’s late-18th-century method of
vaccination, doctors gradually started discovering vaccinesand dealing with pathogens, thus laying the foundations of

2.3.1.

The Foundations of Immunotherapy andChemotherapy
Smallpox has been one of humanity’s greatest enemies,
assaulting the world since ancient times. All the while,
people all over the world have been trying to find ways toprevent it. The Chinese in the Ming Dynasty found that if ahealthy individual was inoculated with pus from the scabs ofan infected individual, the healthy individual would notcontract smallpox. It was also found that dressing a healthy
infant in clothing worn by an infected infant would prevent
contagion. It was further found among nomads in the Persian
region that individuals who had contracted cow pox would
not contract smallpox.
Based on these anecdotes, in 1796 Jenner inoculated aneight-year-old boy with pus collected from the hands of amilkmaid. Two months later, he inoculated the boy withsmallpox, but the boy was not infected. Jenner publishedthese results in a pamphlet in 1798, an epoch-making
publication in the history of human medicine. However,these results appear to have been largely ignored by the
medical community at the time. This is not an isolated
incident; the dawn of modern science saw many outstanding
inventions and discoveries ignored or opposed, unable tooust existing misconceptions.
Nevertheless, this discovery by Jenner laid the foundation
for immunology. Research on immunization as a method oftreatment was carried from the late 19th century onwards,
before the appearance of synthetic drugs (1, 2, 3).

Systematized Survey on the History of Drug Discovery with Technical Development

21

Louis Pasteur, known as the father of modern
microbiology, came up with the idea of fighting invading
microbes with serum containing substances that would kill
the bacteria. In 1888, George Henry Falkiner Nuttall
observed a substance that had a destructive power against
microbes but that lost its activity at 50-55˚C. This became
the basis for theories on liquids in immunology. In 1901,
Jules Jean Baptiste Vincent Bordet (awarded the Nobel Prizein Physiology or Medicine in 1919) was the first to observe
the phenomenon of complement fixation. Around the turn ofthe 20th century, Russian zoologist Elie Metchnikoff
confirmed that macrophages kill microbes. Thus, thefoundation was laid for immunology and advances weremade in research on attenuated vaccines, antitoxin serums
and other areas of immunotherapy.
Pasteur devised this immunization technique from
infectious animal diseases. He successfully tested a fowlcholera vaccine in 1880 and a rabies vaccine in 1885.
Although the rabies vaccine worked for canine rabies as wellas human rabies, there were not many instances of thevaccine or serotherapy working successfully against thehuman rabies pathogen.
By contrast, Robert Koch of Germany took the plunge
into human infectious diseases, but was ultimately
unsuccessful in his efforts with diphtheria, typhoid fever andtuberculosis. Shibasaburō Kitasato studied under Koch anddiscovered an antitoxin for the tetanus bacillus Clostridium
tetani in 1890 with Emil Behring. He later had success withserotherapy, producing antiserum by administering animals
with successive small doses of bacteria. He and Behring used
this method on diphtheria and published their results.
Behring was later awarded the first Nobel Prize inPhysiology or Medicine in 1901 for his research on
diphtheria antitoxin; Kitasato was short-listed, but was notawarded the prize (mentioned previously). One of thereasons for this was that there was no concept at the time ofawarding the Nobel Prize for collaborative research.
From the late 19th century to the early 20th century, thegreatest leading cause of infant mortality in Europe wasdiphtheria, due to myocardial damage caused by thediphtheria toxin once infected. The discovery of diphtheria
antitoxin was a very significant achievement.
Paul Ehrlich entered the field of chemotherapeutics,
having achieved some good results in developing methods
for testing immune serum efficacy and methods for staining
tissue and cells using pigment (1889: director of the Institutefor Serum Research and Serum Testing in Frankfurt). Ehrlich
believed that infectious diseases that could not be treatedwith antiserum or vaccine therapy should be able to betargeted with chemical substances, stating that “the aim ofexperimental therapeutics is to discover a magic bullet thatwill react only to foreign parasites and not affect the host” (1).
Working under Ehrlich, Kiyoshi Shiga discovered apigment (trypan red) in 1904 that would inhibit themultiplication of trypanosomes that cause sleeping sickness
in humans.

22

In 1909, bacteriologist Sahachirō Hata, also working
under Ehrlich, experimented on animals to confirm theeffects of a chemical compound synthesized by Alfred
Bertheim. It was at this time that the relationship wasestablished between synthesis and evaluation in modern drug
discovery terms. Arsenic compound 606 was confirmed tohave a powerful effect; in 1910, German pharmaceuticalcompany Hoechst marketed this compound under the nameof Salvarsan as a specific medicine for syphilis. It is thoughtthat Hata was chosen to work with Ehrlich as a joint
researcher on the challenging task of anti-syphilis treatments
for his long-standing research in Japan on bubonic plagueand communicable disease control. In 1908, Ehrlich wasawarded the Nobel Prize in Physiology or Medicine for his
theory on antigen-antibody reactions (Note 1).
Oswald Schmiedeberg, a forerunner in pharmacology,
discovered in 1878 that muscarine, a crude drug alkloid,
muscarine had a similar effect on the heart as electricalstimulation of the vagus nerve (mentioned previously). He
also reported on the hypnotic properties of urethane in 1885.
He conducted comprehensive research on the drugs andpoisons of the day (experimental research on the medical
efficacy of active ingredients) and in 1883 published thefuture pharmacology classic Fundamentals of Pharmacology.
Well known for taking on and training students from theWest, Schmiedeberg also had a pioneering influence on
pharmacology in Japan, with many Japanese also learning
under him, including Haruo Hayashi (founding chairman of
the Japanese Pharmacological Society) and Kurata
Morishima (Dean of Kyoto University College of Medicine,
pharmacologist and discoverer of many active ingredientsfrom crude drugs).
As pharmacology advanced, pre-existing chemicalcompounds began to be trialed as drugs, resulting in
discoveries of anesthetics (such as chloral hydrate andchloroform) and antianginals (such as amyl nitrite). Later,organic chemists began actively synthesizing a number ofcompounds in search of compounds with powerful medical
efficacy. This led to the discovery of antipyrine, phenacetin,acetanilide and other analgesic-antipyretics.
At the time, Ehrlich gave an address to the German
Chemical Society acknowledging the benefits of medicines,
but criticizing the use of pharmacological ideas for drug
discovery, noting that “drugs discovered by pharmacologicalmethods act on the symptoms of a disease and do not treat
the disease in the true sense” and that “there is no sense inexperimenting without using pathological animals. Quinineand mercury for syphilis are supreme drugs. Pharmacology
has nothing to contribute to this in terms of research methods”(1:234-235).
Although diseases can be caused by pathogens fromoutside the body and disorders within the body, Ehrlich only
focused on diseases caused by pathogens from outside thebody. However, research advances were yet to be made on
diseases caused by disorders within the body and it was not

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchuntil the 1960s onwards that the use of the pathologicalanimals proposed by Ehrlich saw some success on diseases
other than infections.
The basis of modern drug discovery is to find drugs thatkill pathogens in vitro, check their efficacy on infectedanimals and then administer them to patients. However, there
was very little science available in those days on applying
such a system to drugs other than antibacterial(chemotherapeutic) drugs. By contrast, the pathogen
infection model was already soundly tested and so it was thenatural course to take for drug discovery to start with
anti-pathogens (1, 2, 3).
Quite some time later, in 1935, Gerhard Domagk ofGermany discovered that the red dye Prontosil had anantimalarial effect. He also discovered that Prontosil was
also effective on streptococcus; there is a well-known story
that he saved his daughter’s life by administering her with
Prontosil when she contracted streptococcus. Prontosil
became the topic of global attention as a chemotherapeuticequal to Salvarsan for the syphilis spirochete and quinine formalaria.
Later, a group from the Pasteur Institute in France
conducted a thorough study on Prontosil in opposition toGermany. The Domagk faction in Germany conducted
research targeting azo dyes with the idea that “the efficacy ofProntosil lies in the azo dye, the source of the red coloring,which binds to the sulfonamide group”. The French faction
removed the azo group from Prontosil to synthesize a whitesulfonamide, with the idea that “the sulfonamide group isessential, while the azo group is unnecessary”. This
compound had a higher medicinal efficacy and lower toxicity
than the red sulfonamide. Sulfonamide derivatives are easy
to synthesize; on the basis of this information, a successionof sulfa drugs started being developed all around the world.
Prontosil was a so-called “prodrug” (Note 2), demonstrating its
efficacy after metabolizing to its active ingredient, sulfamine(1).
Sulfa drugs is a general term for antibacterial or
chemotherapeutic drugs with a “sulfonamide functionalgroup (-S(=O)2-NR2)”. (They are not called antibiotics since
they are not of biological origin. For the purpose of thisstudy, synthetic compounds with an antibacterial effect aretreated as chemotherapeutic drugs.) Domagk was laterawarded the Nobel Prize in Physiology or Medicine for his
development of Prontosil, although he declined it inaccordance with German state policy at the time (1:265).
According to a general review in 1940, there had been
3000 types of sulfamine compounds synthesized to date,signaling the arrival of the sulfa drug era, with drugs such assulfapyridine and sulfathiazole used on a wide range ofbacterial infections, including Pneumococcus and Shigella(1:267).
Company records indicate that many Japanesepharmaceutical companies also caught hold of theinformation on Prontosil and leapt straight into research,development and trial manufacture, resulting in successful

compound synthesis (4, 5, 6, 7). At the time, Japan had norestrictions on substance patents. Yamanouchi
Pharmaceutical released Gerison® (sulfamine powder) inJapan in 1937, followed by the two-sulfonamide-group
Albasil® (sulfathiazole powder) in 1938. Daiichi
Pharmaceutical released Therapol® in 1937 and thetwo-sulfamine-group Two-Group Therapol® in 1939
(discussed later).
In 1928, Alexander Fleming observed bacteriolysis in apetri dish cultivation of Staphylococcus contaminated with
Penicillium notatum and conjectured that the bacteriolysis
was caused by a substance released by the mold. He named
this substance “penicillin”. While the story is very
well-known, this penicillin was a mixture that could not bemass produced. A project team was organized in 1938 to
isolate and identify the substance and carry out clinical trials.
Mass production was successfully achieved by Howard
Florey and Ernst Chain of the “Oxford group” (8).
The case with penicillin was the first time that a substanceof microbial origin was observed to have a powerfulantibacterial effect, rather than a synthetic antibacterial,
which were the focus of the time. This marked the dawningof antibiotics. Penicillin also had the added benefit of being
easier to use with fewer side effects than the synthetic
antibacterial drugs of the day. With the capability to kill anumber of pathogens that humanity had never been able toconquer, penicillin became a world-saving hero, rescuingcountless patients from all kinds of infections. Penicillin also
saved the lives of many soldiers wounded in the Second
World War. Since then, full-scale efforts have been made toscreen for antibiotics, with research and development
continuing to advance in order to find other mold or fungi
products with powerful medicinal efficacy. In 1945, Fleming,
Florey and Chain were awarded the Nobel Prize inPhysiology or Medicine for their invention of penicillin. The“Oxford group” project formed the basis for the antibiotics
research and development process (9).
In 1882, Robert Koch discovered the pathogen behindtuberculosis, one of humanity’s most troublesome infectious
diseases since ancient times. At the time, the Industrial
Revolution meant workers were converging in urban areas,
with harsh working conditions, poor nutrition and adverse
environments; around 1870, 1% of the population had diedof tuberculosis. After discovering the pathogen, Kochpublished his ideas on “tuberculin treatment” in 1890,
anticipating that it would work for immunotherapy. However,
the effect deteriorated and did not result in a tuberculosis
drug. A number of other compounds emerged at this time,
purported to be effective against various kinds oftuberculosis in the medieval sense, but none of them lived up
to expectations; it was quite a long time after that before atuberculosis drug appeared.

Systematized Survey on the History of Drug Discovery with Technical Development23

Swedish scientist Jörgen Lehmann noticed that salicylic
acid actually promoted the multiplication of the tubercle
bacillus and anticipated that an analogous compound of
salicylic acid would have an inhibitory effect on the bacillus.
This idea is the exact concept behind modern drug discovery.
In 1944, it was finally found that para-aminosalicylic acid(PAS) is effective against the tubercle bacillus. In Japan,
Tanabe Seiyaku started producing this in 1950 (7).

Salvarsan

In 1944, Selman Waksman discovered that ray fungus
contains streptomycin, an antibiotic produced by microbes
and a specific medicine for tuberculosis (Note 3). Streptomycin
showed good efficacy against gram-negative bacteria, against
which penicillin and sulfa drugs had no effect, and had adramatic effect on improving the symptoms of pulmonary
tuberculosis.

Ehrlich and Hata discovered Salvarsan at the beginning ofththe 20 century, although its actual structure was notstdetermined until the beginning of the 21 century.
Salvarsan is a mixture of dimers, trimers and hexamers.

However, in many cases the remaining tubercle bacilli inthe lung lesions developed resistance around 40 days after

Penicillin

Sulfa drugs(sulfonamides/sulfamines)

treatment with streptomycin and the symptoms remerged andstarted to deteriorate even with continued treatment.
PAS, mentioned above, had little effect in treating
tuberculosis on its own, but combined with streptomycin it
improved the treatment rate by inhibiting the emergence ofantibiotic-resistant bacteria, thus making it possible toGeneral sulfonamide group structure:
Sulfa drug is a general term for an
antibacterial or chemotherapeutic
drug with a sulfonamide group.

Penicillin was isolated by Florey
and Chain in 1940; this was a
mixture of penicillin G andpenicillin N.

provide an effective anti-tuberculosis treatment to patients
who previously could only hope and pray for a cure. This
treatment started being used in Japan around 1952 (10).
In 1946, Gerhard Domagk of German pharmaceuticalcompany Bayer, who had discovered the sulfa drug Prontosil,
discovered that isonicotinic acid hydrazide (INH, isoniazid)

Prontosil discovered by Domagk. The active component issulfanilamide. In 1933, German clinician Richard Foerster
reported on its efficacy against Staphylococcus.

was effective against the tubercle bacillus. A triple-drug
regimen of isoniazid, pyrazinamide and streptomycin was
perfected, resulting in a dramatic decrease in deaths from

Fig. 2.5.

Discovery of Chemotherapeutics andAntibiotics.

tuberculosis.
However, even triple-drug therapy was mainly concernedwith inhibiting bacteria. The complete eradication of bacteria
began with the appearance of rifampicin in the 1970s. A“cocktail treatment” of streptomycin added to a triple-drug
regimen of rifampicin, isoniazid and pyrazinamide showed
outstanding results in eradicating tubercle bacilli fromlesions.
Screening for antibiotics was the earliest system used forNote 1: The proper chemical structure of Salvarsan was not
identified until quite recently in 2005. Salvarsan is actually not asingle dimer compound, as per the structure proposed by Ehrlich, but
a mixture of a cyclic trimer and a pentamer; it has been found to act
in the body by oxidizing into monomers (see Figure 2.5. Discovery
of Chemotherapeutics and Antibiotics. The following literature
discusses trimers and pentamers. {Lloyd N.C., Morgan H.W.,
Nicholson B.K. and Ronimus R.S.: The composition of Ehrlich’s
Salvarsan: Resolution of a century-old debate. Angew Chem. Int. Ed.
Engl. 44 941-944 (2005)}).

drug discovery. Researchers would cultivate a particular
microbe in a petri dish, add a compound and determine themedicinal efficacy by observing whether the compound
killed or inhibited the growth of the microbe. This was asimple system of evaluation; it was found in later years that avast amount of information on endogenous diseases inhuman organs is required. The course taken by drug
discovery has been a natural consequence of starting with thedevelopment of chemotherapeutics (9, 10).

24

Note 2: Some drugs have no or little medicinal effect on their own,
but have a powerful medicinal effect once metabolized and activatedin the body. These precursors are called prodrugs.
Note 3: Although Waksman was awarded the Nobel Prize inPhysiology or Medicine in 1952, it was actually medical student
Albert Schatz who did the planning and experimenting to discover
streptomycin. Waksman was his nominal supervisor. Schatz insisted
on being billed as the discoverer; this developed into a lawsuit. The
court ruled that Waksman and Schatz were the co-discoverers of
streptomycin and a settlement was reached.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchReferencestransplanted with testes from another bird. Based on the fact

[1]

Ishizaka T.: Kusuri no Rekishi (History of Medicine).

that microscopy revealed no nerves clinging to the gonads

Nippon Hyoron Sha 225-239 (1979).

and the fact that sperm cells were present, he conjectured that

Singer C. & Underwood E., Sakai S. & Fukase Y.

the gonads had an effect on the emergence of secondary sex(trans.): Igaku no Rekishi (A Short History ofcharacteristics unrelated to the nerves and that the changes

Medicine) Vol. 2. Asakura Publishing Co. (1986).

were triggered by a chemical substance. This developed into

Amano H.: Kusuri no Rekishi (History of Medicine).

the concept of endocrine hormones.

[2]

[3]

Yakuji Nippo (2000).
[4]

[5]

[6]
[7]
[8]
[9]

While alkaloids with various different powerful effects

Yamanouchi Seiyaku Gojūnen-shi (50-year History of

had been extracted from crude drugs, hormones were the first

Yamanouchi Pharmaceutical): Yamanouchi

in vivo substances to be extracted from animal organs. The

Pharmaceutical Co., Ltd. (1975).

adrenal glands and the pancreas were the first target organs.

Daiichi Seiyaku Kyūjūnen-shi (90-year History of

In 1907, Jōkichi Takamine and his assistant Keizō Uenaka

Daiichi Pharmaceutical): Daiichi Pharmaceuticalisolated the first hormone, adrenaline, from the adrenal(2007).

medulla. Prior to that, Edward Albert Sharpey-Schafer andTakeda Nihyakunen-shi (200-year History of Takeda):

George Oliver had found in 1895 that an extract from theTakeda Pharmaceutical Co., Ltd. (1984).

adrenal medulla had vasoconstrictive, hypertensive andTanabe Seiyaku 330-nen Tsū-shi (330-year History ofbrochodilating effects. The target substance was variously

Tanabe Seiyaku): Tanabe Seiyaku Co., Ltd. (2007).

named adrenaline and epinephrine and there was some

Ernst Chain, Howard Florey: Penicillin as acontroversy between Japan and the United States as to who

Chemotherapeutic Agent. Lancet II: 226-228 (1940).

had discovered it first (1, 2:217-220) (mentioned later).

Tsunoda F.: Hekiso / Nihon Penishirin Monogatari

The Industrial Revolution that had begun in the late 18th

(The Story of the Japanese Penicillin – Hekiso).

century led to dramatic developments in the mining andShinchosha (1979).

manufacturing industry, as well as population influx into

[10] Nihon Yakugakukai Hyakunenshi (100-year History of
the Pharmaceutical Society of Japan). The

larger urban areas. Supplying food to support these
populations became a major social issue and prompted

Pharmaceutical Society of Japan (ed.) (1980).

developments in nutritional science. Besides humans, theraising of livestock was also an important issue and studies

2.3.2.

Advances in Endocrine Researchwere carried out on the relationship between food andBy the end of the 19th century, two important keys tonutrition. In 1837, William Prout proposed the idea of three

unravelling the mystery of vital phenomena had been found:main nutrients. The concept of metabolism of in vivo

endocrines and nutrients.

substances came into being in the mid-19th century, as did
the concepts of inorganic salts and vitamins (2).

The idea of incretions from organs having an effect ontissues in the human body was not new; it had been proposedby anatomist Frederik Ruysch in the late 17th century. By the

Insulinmid-19th century, a wealth of research was being carried out

Diabetes is recorded in the ancient Egyptian documenton the adrenal glands, gonads and other endocrine organs in

Papyrus Ebers and is presumed to have been known as a

the form of experimental resections and anatomicaldisease that causes blindness and eventually death at a timeobservations using animal organs. This helped to clarify thewhen humans’ food situation was by no means adequate.

relationship between various endocrine disorders and in vivo

Ancient Indian doctors are also thought to have been aware

substances.

that the urine of sufferers from this disease had a sweet smell.

In 1836, English medical scientist Richard Bright

Medical works from ancient China also have clear

conducted a study on kidney disease, hypertension and heart

descriptions of symptoms including dry mouth, increased

disease. His colleague Thomas Addison discovered

urination and sugar in the urine.

“Addison’s disease”, in which lesions form in the adrenal

This disease was even known in ancient Japan. An ¥80

glands and not enough hormones are produced, eventually

postage stamp was issued in 1994, bearing the image of an

resulting in death. This observation came 60 years before theinsulin crystal and Fujiwara no Michinaga to commemorate

discovery of the hypertensive substance renin. In 1849,

the 15th World Diabetes Congress. It has been conjectured

German anatomist Arnold Berthold found that the crests offrom Shōyūki, the journal of Fujiwara no Sanesuke, that thecastrated roosters would grow to maturity if the bird were

influential Heian-Period figure Fujiwara no Michinaga

Systematized Survey on the History of Drug Discovery with Technical Development25

suffered from diabetes. Mananpō, written in the Kamakuraengineering (mentioned later).

Period, also records a disease with the symptoms of diabetes.
At that time, there were no crude drugs that were effective
against diabetes, nor any method of treating it. It was notthSteroid Hormones
In 1924, Edgar Allen and Edward Doisy experimented on

until the 19 century that the relationship between therats that had had their ovaries removed, injecting them withpancreas and diabetes was recognized and the cause ofan extract containing estrogen (also called female hormone; adiabetes identified.

general term for several hormones). Advances in

In 1864, Paul Langerhans discovered the islets of

endocrinology were based on the phenomenon of symptoms

Langerhans, so named by Gustave-Édouard Laguesse of

caused by the removal of the testes or ovaries improving

France in 1893. In 1889, Oscar Minkowski and Joseph vonwith the administration of substances extracted from gonads.

Mering reported that symptoms similar to those of human

Adolf Friedrich Johann Butenandt isolated estrogen fromdiabetes occurred in dogs with the removal of the pancreas.

the urine of pregnant women in 1929 and androsterone (aIn 1903, Eugene Lindsay Opie reported that a hormone wasmale hormone) from the urine of men in 1931 (He wasproduced by the islets of Langerhans. However, isolating andnominated for the Nobel Prize in Chemistry in 1939, but

identifying the causative agent insulin took some time, due toturned it down in line with Nazi German policy. He was

the fact that insulin is a protein; it was not until 1920 thatawarded the prize after the Second World War). William

insulin was discovered by Frederick Banting and his assistantAllen and George Corner isolated progesterone (a luteal

Charles Best. There was fierce competition at the time tohormone) in 1934. Edward Doisy, who discovered estrogen,discover insulin. In Shin Insulin Monogatari, Kōsaku

was awarded the Nobel Prize in Physiology or Medicine in

Maruyama notes that prior to the discovery by Banting and1943. While these steroid hormones first identified were sex

Best, 400 medical scientists and researchers had attempted tohormones, at the time the gonads were thought to be central

discover insulin, with five of these pulling out after failing onto the phenomenon of reproduction. Later research revealed

the brink of obtaining insulin (3).

the brain-pituitary gland-genitalia system.

Diabetes sufferers show remarkable improvement when

Mayo Clinic chemist Edward Kendall isolated the steroid

treated with the administration of insulin; people marveled at

cortisone from the adrenal cortex (itself inactive, cortisone

this effect the world over (1922). Pharmaceutical companies

activates as it converts into cortisol). Its structure wasimmediately started mass producing substances extracted anddetermined by Tadeus Reichstein. There is a well-known

isolated from bovine and porcine pancreases. Frederick

account of physician Philip Hench of the same clinic

Banting, who discovered insulin, and John Macleod, who

administering cortisone to a 13-year-old girl suffering fromsupported the research, were awarded the Nobel Prize inrheumatism, resulting in a miraculous recovery, earning

Physiology or Medicine in 1923. Although there was somecortisone a reputation as a magic bullet.

objection to Macleod’s being awarded the Nobel Prize,

The effects of the adrenal cortex hormone arehaving only been a financial support and not involved inwide-ranging and their mechanisms of action are not fullyplanning or conducting experiments, Banting would not have

known, but it is currently regarded as an indispensable drug

had any success without his support(4).

capable of achieving complete response against immune andIn 1956, British analytical chemist Frederick Sanger

inflammatory diseases that would otherwise be incurable.

determined the amino acid sequence of insulin and identified

Kendall was awarded the Nobel Prize in Physiology or

the molecular structure of insulin as a peptide with a

Medicine in 1950 for the discovery of the adrenal cortex

molecular weight of 5087 made up of 51 amino acids in two

hormone and his achievements in clarifying its structure andstrands. Sanger was one of the greatest contributing scholars

function, along with Hench and Reichstein (1, 2, 5). It was

to life science and was awarded the Nobel Prize in Chemistry

more technically difficult to isolate unknown substances

twice, for his work on the identification of the structure of

from animal organs than it was to isolate ingredients frominsulin and for his work on DNA sequencing.

crude drugs. Factors included the stability of ingredients, theThe side effects experienced by patients as a result of

quantity of ingredients (biologically active substances in

immunoreaction to the porcine and bovine insulin wereparticular existed in microscopic quantities), the extraction

resolved with the emergence of human insulin. By 1979,

technology and the handling of the proteins; in some cases,

gene recombination technology made it possible to produce

isolation and purification meant waiting for the technology tohuman insulin easily and safely. Keiichi Itakura of Japan wasadvance.

the first in the world to produce insulin using genetic

26

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchReferencesof Strasbourg. Lauded as the father of modern pharmacology,[1] Singer C. & Underwood E., Sakai S. & Fukase Y.

one of the student from abroad that studied under him was(trans.): Igaku no Rekishi (A Short History of Medicine)Vol. 2. Asakura Publishing Co. 539 (1986).

John Abel.
In the United States, the first university course in[2] Ishizaka T.: Kusuri no Rekishi (History of Medicine).
Nippon Hyoron Sha (1979).

pharmacology was established in 1890 at the University ofMichigan; the founding professor was John Abel. Abel built[3] Maruyama K.: Shin Insulin Monogatari (Story of theup a track record of brilliant achievements, including

New Insulin). Tokyo Kagaku Dojin 29-43 (1992).

isolating epinephrine from the adrenal medulla (1898),[4] Wrenshall G., Hetenyi G. and Feasby W., Ninomiya R.

isolating histamine from the pituitary gland (1919) and(trans.): Insulin Monogatari (Story of Insulin). Iwanami
Shoten 52-64 (1965).

crystallizing insulin (1926). One of his students, Reid Hunt,discovered acetylcholine in an adrenal gland extract in 1906
(1, 2, 5, 6)[5] Amano H.: Kusuri no Rekishi (History of Medicine).

.

Yakuji Nippo (2000).
Adrenaline
In 1856, at a time when physiological societies were
2.3.3.

The Basis of Drug Discovery throughPharmacology and Medicinal Chemistry

raising the idea of endocrines, E. F. Alfred Vulpian used acolor staining method he had devised himself to confirm theWhile various chemical compounds have been isolatedpresence of a unique substance secreted by the adrenal

from crude drugs through advances in modern science,

medulla that had very powerful effects in ultra-trace amounts.

advances have also been made in fields for evaluating the
medicinal efficacy of those compounds. The field involving
clarifying the mechanism of action of drugs is called

While researchers from a number of different countries
competed in the attempt to isolate this substance, it wasanother 44 years until success was achieved by Japanesepharmacology; collaborative research relationships havebeen established in this field with synthetic organic chemists
who synthesize drugs. The field of synthetic organic

researchers Jōkichi Takamine and Keizō Uenaka (3, 4).
John Abel, mentioned previously, reported the isolation of
epinephrine in 1897 in a German publication; Jōkichi

chemistry for synthesizing drugs is known as medicinal

Takamine also reported the isolation of adrenaline in 1900.

chemistry.
In 1868, T. Lauder Brunton published a paper entitled “Onthe Use of Nitrite of Amyl in Angina Pectoris”. This isEuropean researchers as well as the pharmaceutical company
Parke-Davis (Note 1), boasting state-of-the-art facilities for thetime, confirmed the results on adrenaline reported by Keizōthought to be the first case of a chemical compound

Uenaka, a young 24-year-old scientist and pharmacist who

synthesized by an organic chemist being used as a drug.
In the 1860s, Thomas Richard Fraser and organic chemist
Alexander Brown examined the relationship between

had just been employed by Takamine. Epinephrine was notextracted using Abel’s method, and Takamine and Uenaka
were named as the discoverers.

chemical structure and medicinal action for a number ofalkaloids (including strychnine, codeine and morphine) using
medicinal chemistry techniques, the basis of modern drug
discovery. They found that despite being structurally similar,
the newly-synthesized analogous compounds had a reverse
effect or antagonistic action (a competing action that negatesthe original action). The information gained from thesederivatives and their medicinal action provided a basis forthe structure-activity relationship and led to the idea of

However, after Takamine’s death, Abel stirred up
controversy in the Johns Hopkins Hospital Bulletin, theAmerican Journal of Physiology, Science and other scientificpublications, saying that his methodology had been stolen by
Takamine and Uenaka. However, Uenaka’s experiment
notebook (Note 2) confirms that Takamine and the teamobtained a crystal in 1900, thus defending their honor.
American academic circles use the name epinephrine to thisday, although in Europe the name adrenaline is used. In

agonists and antagonists.

Japan, however, the name epinephrine was long used as the

The anitmetabolic phenomenon was already known in

official name until it was corrected to adrenaline in thevitaminology and chemotherapy; under the autonomic

Pharmacopeia in 2006. What a story (Note 3)!

nervous system, the theory extended into the field of

In 1894, George Oliver and Edward Albert Schafer foundpharmacology as well. The in vivo substances of notethat the adrenal medulla contains a substance that constricts

included adrenaline, acetylcholine and histamine.
In 1872, Oswald Schmiedeberg (previously mentioned)
became the first professor of pharmacology at the University

the blood vessels in the skin and organs, causing an increasein blood pressure and relaxation of the bronchial tube. This
substance was the same adrenaline that was discovered by

Systematized Survey on the History of Drug Discovery with Technical Development

27

Takamine and Uenaka; its later synthesized analogous

for pharmacology in the United States. These two men latercompound phenylethylamine had an antagonistic action

received the Nobel Prize in Physiology or Medicine in 1936

(agonist action). In the 1930s, these agonists and antagonists

for their achievements in the theory of chemical transmission

were used in a number of studies aimed at clarifying theof nerve impulses (mentioned previously).

medicinal action of the sympathetic nervous system (1, 2, 5, 6).

It was not known at the time whether the transmission of

In contrast to the voluntary somatic nervous system

information at the nerve endings (synapses) was chemical or(motor nerves / sensory nerves), the involuntary autonomic

electrical. On finding that it is relatively dependent on

nervous system controls involuntary functions, such as blood

adrenaline, Loewi hypothesized that neurotransmission

circulation, respiration, digestion,

occurs by means of a chemical substance. He eventuallyperspiration/thermoregulation, endocrine functions andconducted an in vitro experiment in 1921 on two frog hearts,

reproductive functions. The autonomic nervous system

one with the vagus nerve attached and one without, andworks in accord with the endocrine system, a regulatory

conjectured that stimuli are transmitted by a chemicalmechanism using hormones, to maintain homeostasis in thesubstance. Although this experiment is well-known, thebody.

substance was later identified as acetylcholine rather than

The autonomic nervous system comprises sympathetic

adrenaline. Foundational neuropharmacological research was

nerves and parasympathetic nerves; adrenaline andcarried out from 1930 to 1940, with experiments conductednoradrenaline are the neurotransmitters for the sympathetic

on muscarine, an acetylcholine nerve agonist, antagonists

nerves, while acetylcholine is the neurotransmitter for the

tubocurarine and atropine and cholinesterase inhibitor

parasympathetic nerves. Acetylcholine was discovered inphysostigmine (5, 6).
Fig. 2.6 shows the metabolism of noradrenaline at the1914 by Henry Dale; its function as the neurotransmitter for

sympathetic nerve endings.

the parasympathetic nerves was identified by Austrianphysiologist Otto Loewi, whose research laid the foundation

NA: noradrenaline

DOPA

DOPA decarboxylase

Action potential
Dopamine

Dopamine β-hydroxylase

Noradrenaline

Mono Amine Oxidase

Ca+ influx

NE reuptake
Synaptosome

Noradrenaline

NA release

Catechol-O-MethylTransferase
NA receptors(1) DOPA turns into dopamine through the action of DOPA decarboxylase.
Dopamine turns into noradrenaline (NA) through the action of dopamine
β-hydroxylase.
(2) NA is stored in the synaptosome.
(3) NA is released from the synaptosome by electrical stimulus transduction.
(4) The released NA causes various physiological phenomena by acting on thepostsynaptic cell receptors.
(5) NA is metabolized by the catabolic enzyme COMT.
(6) Unmetabolized NA is collected by the presynaptic cell through the reuptake system.
(7) NA is metabolized by the enzyme (MAO) in the synapse.
DOPA: L-3,4-DihyrOxy PhenylAlanine
COMT: Catechol-O-Methyl-Transferase
MAO: Mono Amine Oxidase
Fig. 2.6.

28

Metabolism of Noradrenaline (NA) at the Sympathetic Nerve Endings.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchHistamine
It took a long time to discover histamine, anallergy-induced in vivo substance (8). Many researchers,

carried out instead. The use of genetically engineered
pathological rats and other animals is currently very
restricted.
In the modern era of the 19th century, humans were

including George Oliver at the end of the 19th century,
reported on inducing hypotension in animals by injecting
them with extracts from tissue (thyroid gland, blood, nerve
tissue). While organic chemist Adolf Windaus synthesizedhistamine in 1907 and examined its medicinal action, it was
not until 1911 that it was isolated in an in vivo experiment by
George Barger and Henry Hallett Dale. A succession ofreports on the physiological action of histamine followed. In
1919, John Abel and Bennosuke Kubota reported thepresence of histamine in the pituitary gland andgastrointestinal mucosa (9:562).
Research was also being carried out on the relationshipbetween anaphylaxis and histamine. The final proof came in1932, with two laboratories, Wilhelm Siegmund Feldberg etal. and Carl Albert Dragstedt et al., both reporting thatdamaged tissue releases histamine. Based on the idea ofadrenaline and acetylcholine antagonists, research began on
histamine antagonists in the hopes of finding a substance thatwould protect people from the shock caused by the histamine.
In 1939, Daniel Bovet et al. synthesized an antihistamine
substance (929F). After that, many compounds were foundwith antihistamine effects, establishing the basis for the
structure-activity correlation. Bovet was awarded the Nobel
Prize in Physiology or Medicine for his “discoveries relating
to synthetic compounds that inhibit the action of certain body
substances, and especially their action on the vascular systemand the skeletal muscles” (6).
Advances in Pharmacological Experimentation
The use of animals to test medicinal efficacy dates backthe ancient Greeks. In the 19th century, dogs, cats and birds
were used as laboratory animals. Later, advances inpharmacology began to be achieved through the use of rats inexperiments on the endocrine system as well as to test theefficacy of drugs acting on the central nervous system and toobserve behavioral changes. A number of different species,
including rabbits, dogs, monkeys and chimpanzees, began to
be used in addition to rats, mice and guinea pigs aspathological models for various different human diseases.
The Royal Society for the Prevention of Cruelty to
Animals (RSPCA) was founded in England in 1824; in the
United States, the American Society for the Prevention of
Cruelty to Animals (ASPCA) was founded in 1866. The useof animals in research was long regarded as an exemption to
the related laws; many pathological animals were developed
through hybridization and gene transfer technology.
However, in the mid-20th century, limitations started being
placed on the use of animals for efficacy and safety testing;in vitro experiments (experiments in test tubes using cells,
tissue, enzymes and receptors) began to be increasingly

sometimes used to test medicinal efficacy. In the early days,
there were no adequate means of evaluating efficacy, nor any
adequate safety measures. It was not until 1942 that an idea
similar to the clinical trials of today emerged in a biologicalexperiment on digitalis in humans using a non-invasive
electro-cardiogram to examine the effects of digitalis.
Subsequently, the criteria for experiments on human subjects
were gradually clarified and improved into what they aretoday.
The usual method used for testing the effects of drugs
today is in vitro experimentation using organs or tissue; thisdates back to 1900. Henrick Magnus established this methodof pharmacological experimentation by suspending strips ofsmall intestine in a glass tube (Magnus tube) containing
physiological saline with oxygen bubbling through it andobserving the movements of the tissue using a polygraph(which at the time comprised a rotating drum coated in soot).
In 1904, Jean-François Heymans similarly experimented on
mammalian hearts, while Claude Bernard experimented on
nerve-muscle preparations. While the Magnus tube wassimple, the discovery that tissue and organs could be brought
into a living state in vitro was ground-breaking. This
experimentation technique is still used today (6).
Sterilization and anesthetics revolutionized surgicalprocedures. Anesthetics derived from crude drugs had beenused in Europe, but were not completely effective. In 1846,
William Morton successfully performed a tooth extraction
using ether as an anesthetic; in 1847, James Simpson
successfully performed major obstetric surgery using
chloroform. In 1869, Otto Liebreich hypothesized thatchloral hydrate would have an anesthetic effect because it
releases chloroform in the presence of an alkali. After anumber of clinical trials, he reported it as a new
hypnotic/anesthetic (mentioned previously).
Organic chemists in Germany later synthesized a numberof compounds, including salicylic acid, aspirin, acetanilide,
phenacetin, antipyrine and other antipyretic analgesics (7, 8).
From the late 19th century to the early 20th century,
advances were made in analytics and organic chemistry andbiochemistry was developed. Progress was made in researchon in vivo amino acids and organic acids, proteins andnucleic acid. In 1910, Albrecht Kossel was awarded theNobel Prize in Physiology or Medicine “in recognition of thecontributions to our knowledge of cell chemistry madethrough his work on proteins, including the nucleic
substances”. The Nobel Prize in Chemistry was awarded to
Otto Wallach “in recognition of his services to organic
chemistry and the chemical industry by his pioneer work in
the field of alicyclic compounds”.

Systematized Survey on the History of Drug Discovery with Technical Development

29

Research on diseases continued with advances in
immunology. Charles Richet was awarded the Nobel Prize inPhysiology or Medicine in 1913 “in recognition of his workon anaphylaxis”, while Jules Bordet received the award in1919 “for his discoveries relating to immunity”.
Although these were remarkable scientific developments,
in terms of drug discovery, no outstanding new drugs
emerged until after the Second World War as the modern
drug discovery process was perfected, offering thoroughevaluation of compounds isolated from crude drugs and theirrelated compounds. This is thought to be due to a number ofdifferent factors, such as the fact that the science foranalyzing pathological mechanisms was not yet far enoughadvanced, the fact that there were no clear objectives for the
drugs and the fact that medicinal chemistry lacked anadequate level of technology to synthesize the various
different samples to be evaluated, not to mention the fact that
there was no set methodology for theoretical advances in the
structure-activity correlation and it often depended on
chance.
Note 1: In 1900, Thomas Aldrich of Parke-Davis isolated acompound from the adrenal medulla with the empirical formula of
C9H13NO3. Although this was only CH2 less than the empiricalformula C10H15NO3 of the adrenaline reported by Takamine et al.,Aldrich regarded the two as the same substance, assuming the
Takamine et al. substance to contain impurities. Despite having been
Abel’s assistant, he also considered the empirical formula ofepinephrine C17H15NO4 to contain impurities.
Note 2: Uenaka’s notebook has been registered by the National
Museum of Nature and Science and certified as a future heritage
asset.
Note 3: Horumon Hantā by Mitsuo Ishida goes into more detail on
this course of events (4).

References[1] Oldham F. K, Kelsey F. E, Geiling, E. M. K.: Essential
Pharmacology. Lippincott: Philadelphia (1955).
[2] Holmstedt. B, Liljestrand. G.: Readings inPharmacology. MacMillan: NY (1963).
[3] Dr. Jōkichi Takamine Research Society Bulletin 3:36
(2013).
[4] Ishida M.: Horumon Hantā (Adorenarin no Hakken)(Hormone Hunter (Discovery of Adrenaline)). Kyoto
University Press (2012).
[6] Leake, C.: An Historical Account of Pharmacology to theTwentieth Century. Charles C. Thomas: Springfield, IL(1975).
[7] Bovet, D.: Nobel Lecture. December 11, 1957. In: The
Nobel Foundation: Nobel Lectures in Physiology or
Medicine 1942-1962. Elsevier Publishing Company:
Amsterdam (1964).

30[8] Ishizaka T.: Kusuri no Rekishi (History of Medicine).
Nippon Hyoron Sha (1979).
[9] Singer C. & Underwood E., Sakai S. & Fukase Y.
(trans.): Igaku no Rekishi (A Short History of Medicine)Vol. 2. Asakura Publishing Co. 539 (1986).

2.3.4.

Medicines in Japan (Part 1: Meiji Period to
Second World War)Western medical science and medicines were introduced
to Japan in earnest from the Meiji Period of the late 19th
century onwards. However, even during the Edo Period in
the early 18th century under national seclusion, the study ofWestern knowledge still penetrated Japan and had an effect.
Konyō Aoki was ordered by shogun Tokugawa Yoshimune
to start studying Dutch in 1740. The first autopsy in Japanwas carried out in 1771; observers Genpaku Sugita, Ryōtaku
Maeno and Junan Nakagawa were surprised at how different
the actual organs were from those they had studied in books.
They were very impressed by the detail of the Western book
Ontleedkundige Tafelen and worked on completing its
Japanese translation, Kaitai Shinsho.
In 1823, Dr. Philipp Franz von Siebold came to Japan
from Holland to teach Western medical treatment. He usedaround 230 kinds of crude drugs, including Zingiber (ginger),Mentha (mint), Camphora (camphor), cinnamon bark, gum
arabic and cloves, and is said to have amazed Japanesephysicians with their effectiveness. While there are doubts as
to whether these drugs really had such amazing medicinal
efficacy, there is no doubt that some of the Western
scholarship and science brought to Japan by the Dutch in thelate 18th and early 19th century started laying the foundation
for Japan’s modernization. Another view asserts that theDutch would not have been able to bring the most advanced
medical technology and medicine to Japan, as the Dutch
were not as advanced in chemistry and pharmaceuticalscience as the Germans, the French or the English (1).
An examination of journals and records that describe thedrug situation at that time reveals that according to Koan no
Kusuribako (Medicine Box of Koan) (2:46-47), the drugs usedmost commonly by Dr. Ogata Kōan were “mugwort(anthelmintic from which santonin was later isolated)”,“rhubarb (cathartic, from which sennoside was later isolated;rhubarb is also one of the medicines held at the Shōsō-in andanalysis was performed on the ingredient sennocide)”,“cinnamon bark”, “licorice (from which glycyrrhizin was
isolated)” and “scopolia rhizome”. Dr. Kōan seems to havemainly treated his patients with anthelmintics, laxatives andscopolia rhizome, which acts on the central nervous system.
At the end of the Edo Period in the mid to late 19th century,
people in many different fields came to Japan from overseas,each writing an account of the situation in Japan from theirown perspective. Russian naval captain Vasily Golovnin,taken prisoner by the Japanese in 1811, wrote that “Japanese

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchphysicians pay very little attention to the regimen of the sick”
and that “medicine could not operate to advantage with suchfood”. He also noted that “all Japanese carried antidiarrheals”(Memoirs of a Captivity in Japan). Commodore Matthew
Perry of the United States East India Squadron wrote in his
Narrative of the Expedition of an American Squadron to the
China Seas and Japan that “the native physicians… have notavailed themselves at all of post mortem examinations…
superstition is in the way. …Without such examinations, it isobvious that the knowledge of the physician and surgeon
must be but imperfect at best. …Their drugs are mostly
animal and vegetable; they are too little acquainted withchemistry to venture upon mineral remedies. They study
medical botany, however, with great attention, and theirremedies are said to be generally efficacious” (2:118-124).
Dutch physician Johannes Pompe van Meerdervoort
arrived in Nagasaki in 1857 and spent five years in Japan. He
had a significant impact on Japan at the dawning of a new
era in medical treatment. Pompe van Meerdervoort appealed
to the shogun with the need to establish hospitals. In his bookVijf Jaren in Japan, he noted that “surgery is done using
salves; there is no understanding at all of surgical procedures.
Knowledge of science is nonexistent, but there was highenthusiasm for learning among the young medical students.”
Pompe van Meerdervoort also wrote of ancient Japanese
medicine that “unfortunately I could not even glean any
medical principles from them, as I believe there is a lack oftraining schools”, noting that “the common people treat theirown ailments, using moxa and acupuncture to release thetoxic gases from within the body” (3:301-302).
British consul-general Rutherford Alcock came to Japan
in 1859. In his work The Capital of the Tycoon, he noted that
“There are many skin diseases in Japan. People go to hot
springs for treatment. The home remedy of ‘moxa’ isperformed once a year to eradicate all kinds of diseases”(2:118-124). These records provide a good estimation of the
medicine and medical treatment situation in Japan at the endof the Edo Period.
Around the time that advances in modern science in theWest were contributing to the isolation of
medicinally-efficacious active substances from various crude
drugs and the discovery of pathogenic microbes, theJapanese government was transitioning to the new Meiji
administration. An examination of Meiji-era trends inJapanese pharmaceutical companies reveals a transition by
drug wholesalers from Chinese medicine to Western
medicine once the isolation period ended and an increase intransactions of drugs imported from the West. The company
histories of various drug developers indicate that after the
Meiji Reformation they faced a monumental decision ofwhether to keep working with Chinese and Japanese
medicine or to switch to Western medicine. However, manyrecords state that companies “were zealous to absorb
knowledge of Western medicines and actively absorbed the
new knowledge” (5, 6).
With the influx of Western medicine, counterfeit drugs
and low-purity medications also began to appear on themarket. The Meiji government established pharmaceuticallaboratories for testing imported drugs in an effort to ensure
the supply of genuine drugs (1874-1876). In 1889, thegovernment promulgated the Regulations on Pharmaceutical
Operations and Products.
A medical system, including a licensing system forphysicians, had been announced in 1874, while thePharmacopeia, which set the criteria for medical andpharmaceutical products, had been established in 1886.
Aware that they had to do more than just import drugs toensure the quality of Western medicines, drug wholesalers
started transitioning into specialized manufacturers ofWestern medicines. The major drug wholesalers Tanabe
Gorobē, Takeda Chōbei and Shiono Gisaburō each started
their own drug manufacturing enterprises, although many of
their early products were poorly manufactured (iodine wasparticularly problematic). Realizing that to compete against
the West they had no choice but to establish agovernment-subsidized pharmaceutical company, in 1883
they jointly established Dainippon Pharmaceutical withsupport from the government.
This was Japan’s first pharmaceutical company. Domestic
drug production started with Nagayoshi Nagai, thediscoverer of ephedrine, as chief of drug manufacture,overseeing everything from installing machinery to
producing medicines. Meanwhile, influential drug brokers
and wholesalers in Osaka established Osaka Pharmaceuticalin 1897. However, the operation of Dainippon
Pharmaceutical was impeded by state-influenced company
bureaucracy and in 1899 it was taken over by Osaka
Pharmaceutical (8). Dainippon Pharmaceutical continued
working on the formulation of ephedrine, later launching thisJapanese discovery in 1927 as the bronchodilator andantitussive “Nagai” (1, 4, 8).
Adrenaline, discovered by Jōkichi Takamine, wasre-imported back to Japan in 1902, having already beenlaunched on the American market. Sankyo Shoten hadlaunched Takadiastase, another of Takamine’s discoveries, in
1898. Takadiastase is a digestive drug that is frequently
mentioned in Sōseki Natsume’s novel I Am a Cat. In 1913,
Jōkichi Takamine was appointed the first president ofSankyo Shoten.
Diastase (amylase) is a highly active enzyme thathydrolyzes starch into disaccharides and monosaccharides. It
is used in fermentation-related industries. Jōkichi Takamine
and Tetsukichi Shimizu successfully extracted and powdereddiastase from koji mold Aspergillus oryzae and patented it in
the United States in 1894. This is the product Takadiastase.
The product was marketed in the United States the following
year by George Davis of Parke-Davis as a powdereddigestive medicine (7). Until then, all extracts had been
concentrated syrups, which were troublesome andinconsistent to deal with. The powdered form also made iteasier to combine with other drugs, making it a popular
product since it was first launched and it is still available on
the market today (18).
Vitamin B, first discovered from rice bran by Umetarō
Suzuki in 1910, was marketed by Sankyo Shoten as
Oryzanin®. Later, this drug was found to be effective against
beriberi, a very serious disease in Japan at the time, and thenumber of patients suffering from beriberi steadily began to

Systematized Survey on the History of Drug Discovery with Technical Development31decline. While all kinds of vitamin pills were available on themarket in the early 1940s before the Pacific War broke out,
there was even greater credence in vitamins after the war andcompanies started researching and discovering thiamine (B1)derivatives (mentioned later).
The revision of the Patent Act in 1909 and the adoption of
the process patenting system made it possible for thedomestic pharmaceutical industry to adapt the processes used
for new drugs developed overseas by more advanced nations
and market the products in Japan provided they had been
produced in Japan. As a result, research and development of
new drugs in Japan fell behind. The outbreak of the FirstWorld War in 1914 made it difficult to import drugs from
Germany and other countries. The resulting sudden steep risein the cost of Western drugs created a greater need fordomestic production. The government regulated the medical
and pharmaceutical products leaving the country andprovided financial incentives for pharmaceutical products,
including allowing the use of German patents as a wartime
exception (International Property Act in Wartime).
Manufacture of vital drugs began in earnest, including
Salvarsan (antisyphilitic), salicylic acid, sulfa drugs, local
anesthetics, anesthetics and anticonvulsants. The domestic
production of Salvarsan in particular sparked intensecompetition, drawing in the best Japanese technology andexpertise of the day.
Dr. Katsuzaemon Keimatsu, former director of the
medical division of the South Manchuria Railway Central
Experimental Laboratory, started working on a Salvarsan
prototype in January 1915. By April, he had successfully
synthesized it and started commercial production in Japan.
He established “Arsemin Shokai” (which became Daiichi
Pharmaceutical in 1918) and launched Salvarsan under thebrand name of Arsemin®. However, Salvarsan was
administered by injection and, being insoluble, would cause
pain to patients if too much was administered. The
formulation was improved and marketed as Neo-Arsemin®.
Daiichi Pharmaceutical devised a dosage form, whichsignificantly increased sales.
Umetarō Suzuki of Tokyo Imperial University College ofAgriculture established a method for manufacturing
Salvarsan in March 1915, assisted by a grant from the
Ministry of Finance. The product was launched by Sankyo in
September that year under the brand name of Arsaminol®.
Tōru Iwadare, under the supervision of Prof. Kōchi
Matsubara of the Tokyo Imperial University College of
Science, completed a prototype in April 1915 and invested
his own funds to have it launched by Banyu Ltd. (later
Banyu Pharmaceutical) under the brand name of Eramisol®.
Dr. Mitsuru Kuhara of the Kyoto Imperial University
College of Science and Engineering (and the first presidentof the Chemical Society of Japan) completed a prototype in
May 1915 and had it marketed by Kyoto Shinyakudo (nowNippon Shinyaku) as Saviol®.
This flurry of developmental activity gives us a sense of
the energy and vigor befitting the dawning era of domestic
production of new drugs (12:5-7, 17:252-253).
Domestic production of sulfa drugs in the 1920s and1930s in the early Showa Period saw eight major industry
players playing off against each other (8, 9). Daiichi
Pharmaceutical, established in 1918, marketed the first
domestically-produced sulfa drug in 1937 under the brand32

name of Therapol®. Therapol was synthesized by Kazuo
Miyatake not long after he started working there; he laterwent on to become the company president. According to thecompany’s history, the chief engineer saw the compound in
the German organic chemistry journal Justus Liebigs
Annalen der Chemie and said to Miyatake, “I have seen thisstuff – could you make it at once?” Miyake then “made it as
quickly as possible. There were no animal experiments in
those days. This was Therapol®, the first such product to bemade domestically” (12).
At almost the same time, Yamanouchi Pharmaceuticalmarketed Gerison® (sulfamine powder) in 1937 andproduced the two-sulfonamide-group Albasil® the following
year. By 1949, Yamanouchi Pharmaceutical was the top
producer of sulfa drugs in Japan (14).
Daiichi Pharmaceutical also released thetwo-sulfamine-group Two-Group Therapol in 1939, followedby the sulfapyridine Therapyridine® in 1942.
Takeda Pharmaceutical, Banyu Pharmaceutical, Shionogi
Seiyaku, Tanabe Seiyaku, Sankyo and Dainippon
Pharmaceutical all started researching and developing sulfa
drugs at around the same time, each marketing their own
respective products.
Tanabe Seiyaku launched the topical non-steroidal
anti-inflammatory Salomethyl® with methyl salicylate as themain ingredient in 1921 after having found out that methyl
salicylate was the main ingredient in the well-known French
pain-relief ointment Baume Bengué® (5).
After the First World War, the pharmaceutical industry nolonger had to depend on imported products as it had done
and was able to use domestically-produced drugs as its
production staple. However, the government’s policy ofprioritizing domestic production through initiatives such as
the process patenting system for overseas drugs came at theexpense of investment into Japanese research anddevelopment of new drugs, thereby hindering any new drug
inventions by the Japanese.
In the 1930s and 1940s, there was a rapid increase inantiseptics formulated from acridine derivatives, azo dyes
and organomercury compounds; these were marketed by
Banyu Pharmaceutical, Takeda Pharmaceutical, Daiichi
Pharmaceutical, Tanabe Seiyaku, Yamanouchi
Pharmaceutical, Shionogi Seiyaku and other companies (5, 6, 7,
11, 12, 13).
The 1931 edition of Jōyō Shinyaku Shū (Nippon Shinyakued.) reveals the common diseases of the time, as well as the
medical and pharmaceutical products used to treat them.
According to this data, drugs for infections accounted for
30% of all drugs (see Figure 2.10). There were manydermatological, otolaryngological and gynecological drugs,
while analgesics and antipyretics accounted for 10% andanticonvulsants 9%. There was not yet the same mention ofdrugs for treating diabetes, hypertension, hyperlipidemia orother 21st-century lifestyle-related diseases (9).
(Table 2.4 shows the types and ratios (Note) of drugs
administered in 1931 and has been re-tabulated by the author
based on information taken from Jōyō Shinyaku Shū (Nippon
Shinyaku ed.) and Nihon Iyaku Sangyō-shi (pp.74-75).)

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchTable 2.4 Types and Ratios of Drugs Administered in
1931(1) Antimicrobial / chemotherapeutic /antibiotic

Types

Ratio

570

30%

(2) Surgery related

945%(3) Analgesic / antipyretic / anticonvulsant

189

10%

(4) Gastrointestinal

170

9%

(5) Lifestyle-related disease201%(6) Circulatory / antianginal

139

7%

(7) Antitussive

734%(8) Vitamins / nutritional supplements

173

9%

(9) Other (dermatological /otolaryngological / gynecological)

34%

was marketed by Dainippon Pharmaceutical in 1941 (4, 8).
The main thrust of drug discovery in postwar Japan was
research and development of chemotherapeutic drugs (Note 2).
This became the mainstay of the Japanese pharmaceuticalindustry, with universities, government research institutions
and private companies discovering a succession of new
antibiotics and synthetic antimicrobials. This trend continued
until the 1990s, as Japan topped the world in theadministration of antibiotics, antimicrobials and otherchemotherapeutic drugs.
Note 1: In 1943, the German clinical bulletin Wiener Klinische
Wochenschrift containing news of the “antimicrobial substance penicillin
obtained from microbes” was brought by the U-boat 511 from Axis
power Germany; in 1944, the news that “Churchill made a complete
recovery from pneumonia with penicillin” was brought to Japan by the

The Japanese also had issues with the treatment ofsewerage; many people carried roundworm and threadworm
from ancient to early modern times. Since the discovery of
santonin from mugwort in 1830, it has been used by many
researchers in pharmacology and clinical studies. In Japan,
Hisomu Ichinose and Katsura Takada investigated ways to
extract santonin from sea wormwood; domestic production
started in 1929 and it has been used to eradicate roundworm
since then (15). In 1953, Tsunematsu Takemoto extracted
kainic acid from the crude drug red algae Digenea simplex(16). While kainic acid is an amino acid and used for
eradicating roundworm and threadworm, it is known to bindto the glutamate receptors, thereby increasing nerve
stimulation, causing paralysis.
Once news of the curative effects of penicillin reachedJapan from Western Europe despite it being wartime (Note 1),collaborative research began in the public and private sectors,
including research by Hamao Umezawa, promoted by Major
Katsuhiko Inagaki of the Army Medical College. The
Penicillin Committee was inaugurated in 1944, comprising
members from the government and the academic world, andindustrial production of penicillin began in December 1944
with the country still at war. Industrial production started at
the Morinaga Food Industry factory at Mishima; Banyu
Pharmaceutical also started manufacturing it not long after
that. By 1945, Japan had gone from a penicillin production
capacity of several dozen bottles a day to around 200 bottles
a day. According to Hekiso / Nihon Penishirin Monogatari,“wartime production peaked in August 1945 at the end of thewar”. There is no record of the production volume; most of itis presumed to have been used on the battlefield (10).
While the 1930s saw the start of domestic production,
there were few original Japanese drugs manufactured at thattime; it was not until after the war that new drugs invented
by the Japanese began to appear. Notwithstanding, Japan did
make some achievements during this time, including thediscovery of the cardiotonic vitacampher by Kenzō Tamura
and Morizō Ishidate and the discovery of analeptic amines asa result of ephedrine research by Yukito Ōta and Fujio
Egami. Incidentally, records indicate that the analeptic amine
Philopon® was announced in the Journal of thePharmaceutical Society of Japan, Vol. 139 in 1894 by
Nagayoshi Nagai as “ephedra research substance 33” andAsahi Shimbun Buenos Aires correspondent. This marked the beginningof penicillin development in Japan. Although these are well-known
stories, the medical journal was not in fact brought to Japan by a German
U-boat. During the Second World War, Japan sent five submarines toGermany, three of which made it. Hekiso / Nihon Penishirin Monogatariconfirms that the information was brought back to Japan by the I-8, theonly one of these submarines to return to Japan. At Churchill’s request,
he was actually treated with sulfa drugs (or sulfon drugs, as the German
reading was more prevalent at the time), which had proven effectiveness,rather than penicillin (10).
Note 2: Chemotherapeutic treatment refers to the treatment of infectious
diseases using chemical drugs. Antibiotics refers to “antibacterial,
antifungal, antiviral and anticancer drugs derived from substances
produced by microbes”. In this paper, chemotherapeutic drugs include
antibacterial, antifungal, antiviral and anticancer drugs derived fromchemical drugs.

References[1] Amano H.: Kusuri no Rekishi (History of Medicine).
Yakuji Nippo (2000).
[2] Yoneda K. Kōan no Kusuribako (Medicine Box ofKoan). Osaka University Press 46-67 (2001).
[3] Numata J. & Arase S. (co-trans.): Ponpe Nihon Taizai
Kenbunki (Vijif Jaren in Japan). Yushodo (1968).
[4] Dainippon Seiyaku Hyakunen-shi (100-year History ofDainippon Pharmaceutical): Dainippon PharmaceuticalCo., Ltd. 13-15 (1998).
[5] Tanabe Seiyaku 330-nen Tsū-shi (330-year History of
Tanabe Seiyaku): Tanabe Seiyaku Co., Ltd. (2007).
[6] Takeda Nihyakunen-shi (200-year History of Takeda):
Takeda Pharmaceutical Co., Ltd. (1984).
[7] Sankyō Haykunen-shi (100-year History of Sankyo):Sankyo Co., Ltd. 20-28 (2000), reference p.77.
[8] Nihon Yakugakukai Hyakunenshi (100-year History of
the Pharmaceutical Society of Japan). The
Pharmaceutical Society of Japan (ed.) 352-354 (1980).
[9] Nihon Iyakuhin Sangyō-shi (History of the JapanesePharmaceutical Industry): The Japanese Society for
History of Pharmacy (ed.) 80-84 (1995).

Systematized Survey on the History of Drug Discovery with Technical Development33[10] Tsunoda F.: Hekiso / Nihon Penishirin Monogatari (The
Story of the Japanese Penicillin – Hekiso). Shinchosha
133-140 (1979).
[11] Yoshitomi Seiyaku Gojūnen no Ayumi (50-year History
of Yoshitomi Pharmaceutical Industries). Yoshitomi
Pharmaceutical Industries, Ltd. (1990).
[12] Daiichi Seiyaku Kyūjūnen-shi (90-year History ofDaiichi Pharmaceutical): Daiichi Pharmaceutical(2007).
[13] Kōwa Hyakunen-shi (100-year History of Kowa): Kowa
Co., Ltd. (2007).
[14] Yamanouchi Seiyaku Gojūnen-shi (50-year History of
Yamanouchi Pharmaceutical): Yamanouchi
Pharmaceutical Co., Ltd. (1975).
[15] Iyakuhin Intabyū Fōmu (Drug interview form). Santonin.
Nippon Shinyaku (2009).
[16] Murukami S., Takemoto T., Shimizu Z.: Studies on the
Effective Principles of Digenea simplex Aq. I.
Yakugaku Zasshi 73 (9): 1026-1028 (1953).
[17] Okazaki K.: Kusuri no Rekishi (History of Medicine).
Kodansha (1976).
[18] Dr. Jōkichi Takamine Research Society Bulletin 3:
35-36 (2013).

2.4 From New Medicines to Improved
Medicines and Innovative Medicines
2.4.1.

Medicines in Japan (Part 2: Post-Second
World War)As previously mentioned, development progress wasmade in postwar Japan on antibiotics, chemotherapeutic
drugs and vitamins, the foundation having already been laid.
Given the fact that the two leading causes of death in Japan
since the late 19th century were infectious diseases andberiberi, it would have been only natural to start postwar
drug developments with vitamins and drugs to fightinfection.
Although pharmaceutical production started up again soonafter the war as drug production facilities had not been as
hard-hit by war damage as other industries, production
volumes were small due to shortages of ingredients andmaterials. Meanwhile, the demand for medical andpharmaceutical products increased dramatically after the war
due to the poor public health situation. With inadequate
public health, drugs such as penicillin and sulfamine were
designated as high-priority bacterial pharmaceuticals, withpriority given to their production. There was also a demandfor increased production of dermatological drugs as well as
local anesthetics, analgesics and anticonvulsants, which werein high demand in surgery, ophthalmology and dentistry.
Regulated distribution of medical and pharmaceuticalproducts continued until 1952.
Around 35 new Japanese drugs (new ingredients) wererecognized in the 1950s, including 10 antibiotics andchemotherapeutic drugs, 3 bacteria-derived anticancer drugs
and 3 vitamin formulations. The same trend continued in the
1960s, with another 35 new Japanese drugs recognized,
including 9 antibiotics and chemotherapeutic drugs, 7
vitamin formulations and 2 anticancer drugs (1).

34

Social demand aside, companies were also competing
technologically to produce improved drugs from theavailable lead compounds for chemotherapeutic drugs andantibiotics, having honed their methods of evaluation toperfection. The situation was the same for vitamins as well.
(* The difference between drug production and drug discovery:
Up until the 1980s, companies in the pharmaceutical industry
were often referred to as drug manufacturing companies; in the
1990s, as drug research and development began to require agreater accumulation of science and technology (system science),
the research and development of new drugs began to be referred
to as “drug discovery” rather than “drug production”. Companies
that focused on discovering new drugs began to be referred to as
drug discovery companies. Currently, the research anddevelopment of new drugs, including formulation improvementand drug delivery systems (DDS), is often referred to as drug
production.)

Antibiotics
Research and development on penicillin continued toprogress after the war. The Japan Penicillin Research
Association was founded in 1946, while the Japan Penicillin
Association was established around the same time by privatecompanies planning to manufacture the product. There were
39 founding member companies, many of them principally
engaged industries other than pharmaceuticals, such as food,brewing, chemistry and spinning.
The production of penicillin required chemicalengineering technology. Pharmaceutical companies lacked
the experience and facilities, prompting companies from thechemical, food and brewing industries to expand into the
production of antibiotics. At the three-year commemorationof the Japan Penicillin Association in 1949, Captain Samsonof the GHQ said in his congratulatory address, “There arepresently only three countries in the world that are able tosupply their own penicillin. Japan is one of them. Three
years ago I asked you to ‘meet your domestic demand’ and to‘make first-rate penicillin’ and you have succeededadmirably. I would like to make a third request of you:export it to the world” (2:225-226). This came true the following
year. The outbreak of the Korean War raised the demand for
penicillin; with the American military purchasing it,
penicillin production increased dramatically and overseas
exports began. While this was partly due to luck, it also
indicates the superiority of Japanese fermentation andchemical engineering technology.
Streptomycin production required even larger
fermentation equipment and facilities; the pharmaceuticalcompanies again lacked the necessary experience andfacilities. Domestic production began in 1950 with licenses
granted to five organizations in other industries (Meiji Seika,
Kyowa Hakko, Kaken Chemicals, Shimane Chemical and the
Nippon Institute for Biological Science).
As antibiotics began to replace chemotherapeutic drugs,
signs began to appear of antibiotic overuse. Incidents ofdeath by penicillin shock in 1956 called product quality andadministration methods into investigation. In 1958, Hamao
Umezawa (National Institute of Health) and Meiji Seika
developed the epoch-making antibiotic kanamycin using

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchdomestic technology, although other newly-developed
antibiotics were later imported from overseas. The
successive appearance of penicillin-resistant bacteria andother antibiotic-resistant bacteria meant the Japanese drug
discovery industry had to progress from developing
first-generation antibiotics to developing second- andthird-generation antibiotics.
Many of Japan’s developments in antibiotics andchemotherapeutic drugs were world-class new drugs. This isa very significant area in the history of drug discovery,
although for the purposes of this paper these are summarized
together under “lifestyle-related diseases” rather than
discussed individually in detail.
Vitamins
While it is understandable amidst postwar food shortages
that beriberi ranked as one of the top two leading causes ofdeath alongside tuberculosis, it may be surprising that all tenof the new vitamin formulations mentioned previously werethiamine (vitamin B1) derivatives.
Postwar Japan was very receptive to vitamin formulations
to combat nutritional deficiencies stemming from foodshortages. During this time, many different companies weremarketing multivitamin formulations made up of all kinds ofvitamins, sparking the over-the-counter vitamin boom.
Vitamin formulations remained the highest-selling
pharmaceutical product in postwar Japan for 12 years (3) (seeTable 2.5).
A succession of products hit the market. Takeda
Pharmaceutical launched Panvitan® in 1950, while Tokyo
Tanabe Seiyaku launched Vitaplex® and Taisho
Pharmaceutical launched Vitacolin® in 1951, Shionogi
Seiyaku launched Popon-S® in 1952 and Sankyo launched
Minevital® in 1953.
In 1952, Motonori Fujiwara et al. of the Kyoto University
Faculty of Medicine discovered allithiamine, comprising
vitamin B1 bonded to alliin, a substance found in garlic.
They gained some attention for their theory that this would
be effective against arthritis. Backed by this theory, Taizō
Matsukawa et al. of Takeda Pharmaceutical developed theactive vitamin B1 prosulthiamine (Alinamin®) in 1954. This
sparked competition to develop new vitamins, such as
octotiamine (Noivita®) by Fujisawa Pharmaceutical andbenfotiamine by Sankyo in 1961, bisbentiamine (Beston®) byTanabe Seiyaku in 1962, cetotiamine hydrochloride(Dicetamin®) by Shionogi Seiyaku in 1965, cycotiamine(Cometamin®) by Yamanouchi Pharmaceutical in 1966 andbisibuthiamine by Taisho Pharmaceutical in 1967, each new
drug being approved by the Ministry of Health and Welfare.
As a result, pharmaceutical companies made significant
profits from vitamin formulations and were able to invest
those profits into establishing research laboratories for thepharmaceutical industry (1, 3).

Table 2.5 Pharmaceutical Products Sales in Postwar
Japan

Year

¥100 million

1957
1958
1959
1960
1961
1962
1963
1964
1965
1966
1967
1968
1969
1970

1,251
1,345
1,493
1,760
2,181
2,656
3,411
4,232
4,576
5,071
5,633
6,890
8,425
10,253

Product with highest
production volume
antibiotics
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
vitamins
antibiotics

Anticancer Drugs
Following the Second World War, government research
institutions joined forces with private companies in researchon cancer, which had rapidly rose in incidence to become the
top leading cause of death by 1979. Several effective
anticancer drugs were discovered by furthering the researchdone on antibiotics and antibacterial drugs in the 1950s and1960s.
Sarkomycin was discovered by Hamao Umezawa(National Institute of Health & Meiji Seika) in 1954, whilemitomycin was discovered by Tōju Hata (Kitasato Institute& Kyowa Hakko) in 1955. These drugs are well known as
typical early antibiotic-type anticancer drugs. The anticancer
drugs of the day were nonselective, inhibiting the functional
activity of normal cells as well as cancer cells; many
inhibited cell division and many had very strong side effects.
Later, early detection and surgical removal became the mainmeans of treating cancer, while rapid advances in molecularbiology and molecular cytology in the latter half of the 20th
century enabled science to identify cancer-causing
mechanisms. What had previously been lumped together
under the name of “cancer” was actually found to be theresult of several stages of complex mechanisms at work.
Scientists began to understand that cancer could not be
explained as the result of a single mechanism like otherdiseases (although, of course, many other diseases are
likewise not the result of one simple mechanism).
Advances in genetic engineering gradually revealed that
there are different causes for types of cancers and that there
are differences between individual patients due to genetics.
The field of oncology, one of the major focal areas for the
future, is seeing significant results by drug companies using
advanced biotechnology to develop new drugs. Antibody
formulation is one such development that is bringing a ray ofhope into the field of oncology.

Systematized Survey on the History of Drug Discovery with Technical Development

35

Social Background to the Pharmaceutical Industry
The stability of the Japanese postwar economy was incrisis due to deflation. The outbreak of the Korean War in1950 brought with it a sudden demand for vast amounts ofmunitions and strategic resources; these special
procurements caused a boom in the Japanese economy.
Following this, the pharmaceutical industry entered an age offree competition.
Although the Japanese economy plateaued for a while
after the Korean War, a rapid increase in exports in 1955
caused another economic boom. During this time,
pharmaceutical company production divisions started out innew directions of technological innovation, capital
investment and advances in automation. In 1956, drug
production yield rose to ¥103.7 billion, the first time it had
exceeded ¥100 billion, a 16% increase from the previous
year. In 1957, the Japanese economy was showing signs of arecession, but this had little impact on the pharmaceuticalindustry, which continued at a growth rate of 21% resulting
in a drug production yield of ¥125.1 billion (3, 4).
Japan implemented a national health insurance program in1927 and by 1945 it had 4 million members. In 1958, theNational Health Insurance Act was amended to makemembership obligatory; by 1961, it had been implemented
across the entire country and medical insurance for all
citizens had been achieved. This boosted the medical
examination rate and also increased the drug production
yield. These figures grew by more than 20% each year from¥176 billion in 1960 to ¥457.6 billion by 1965 (see Figure2.7) (3).
Drug production yield:¥1 million

Rapid
economic
growth period

Korean War
Nationwide medical
insurance

Fig. 2.7.

Trends in Pharmaceutical Industry
Production Yield.

The pharmaceutical industry in Japan was historically not“new drug oriented”. At that point in time, the mechanisms
causing many of the world’s diseases had not yet been fully
identified and the process of research and development for
drug discovery was by no means perfect. All the Japanesepharmaceutical industry had perfected was the ability to
re-create pharmaceutical products imported from the West.
Unlike in the West, patented in Japan were granted based on
production methods. A product could be patented as long asa different method of production was used to produce it. In
the 1950s, pharmaceutical products in all different fields
were being introduced, from antibiotics, tuberculosis
remedies and sulfa drugs through to antihistamines,

36

hormones and psychoneurotic drugs. By contrast, only a few
drugs were being produced through derived technology,
including kanamycin (Meiji Seika), Alinamin (Takeda
Pharmaceutical), Sinomin (Shionogi Seiyaku) and Adona(Tanabe Seiyaku).
After this had continued for some time, a substancepatenting system was adopted in 1976. Drug production
companies had to make the shift from the existing researchand development approach, which was based arounddeveloping imitations of known pharmaceutical products
using improved production methods, to one of developing
new products, thus metamorphosing into so-called drug
discovery companies.
In the 1960s, people were becoming highly safety
conscious and Japan saw the emergence of a major social
issue: pollution and contamination caused by the rapid
industrial development during the postwar economic boom.
Safety evaluation criteria were far from perfect in Japan in
the 1950s and 1960s; in some cases, data taken fromoverseas was all that could be used for approval. The
pharmaceutical industry experienced a succession of major“incidents of harmful side effects” and people started paying
close attention to the safety of medical and pharmaceuticalproducts. Eventually, even vitamins and health supplements
came under scrutiny, despite having long been consumed inlarge quantities.
There was a succession of incidents involving serious side
effects or even death in large numbers of patients, including
the penicillin shock in 1950, the global thalidomide scandal
in 1959, subacute myelo-optico-neuropathy (SMON) in
1955-1970, chloroquine retinopathy in 1962-1971 and theampoule cold medicine incident in 1964 (see Table 2.6). Thissequence of harmful side effects incidents made people think
about the state of medicines in Japan. The criteria for drug
discovery were carefully reexamined as a countermeasureagainst harmful side effects from drugs, with increasing
demand for safety testing.
The Pharmaceutical Affairs Act was also amended as aresult of these incidents. This Act sets the criteria for theadministration of pharmaceutical products, including thelicensing of medical and pharmaceutical products. It wasamended after the war in 1948 and in 1961; however, theamended version lacked provision for the “efficacy of drugs”
and the “safety of drugs”. The amendment to the Act in 1979
clearly specified its “aim to ensure quality, efficacy andsafety”, reflecting the public opinion of the time (3).
The Good Manufacturing Practice (GMP) Regulations for
Manufacturing Control and Quality Control of Drugs wereenacted in 1980, followed by the Good Laboratory Practice(GLP) Regulations for Conducting Non-Clinical Drug Safety
Trials in 1983. The safety trials required for applying for
production approval from the Ministry of Health and Welfare(now Ministry of Health, Labour and Welfare) had to be
carried out in accordance with GLP.
However, the side effect safety of internal medicines
cannot be verified by restricted animal tests or byadministering them to limited numbers of patients. The
criteria for safety testing continued to increase for decades
afterwards as companies continued to add their own criteria
as well as those directed by the government.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchTable 2.6 Drug Side Effect Incidents: Major Side-Effect Incidents in Japan

Incident Period
1950 - 1955
1959 - 1962
1964 - 1965
1955 - 1970
1965 - 1970
1962 - 1971
1970 - 1975
1972 - 1986
1983 - 1987

Incident
Penicillin shockThalidomide scandal
Ampoule cold
medicine
SMON
Coralgil incident
Chloroquine
retinopathy
Myositisis
Vitamin K injection
shock
Hopateencephalopathy

Cause
Penicillin
Thalidomide
Pyrine drugs

Shock
Birth defects
Shock

Number of victims(confirmed)
100 affected>309 affected>700 affected; 11 deaths

Quinoform
formulation
Coralgil
Chloroquine

Neuropathy

11,033 affected

Systemic lipidosis
Visual impairment andvision loss
Injection site muscle
contraction
Shock>20 deaths; >1,000 affected>3,000 affected

Metabolicencephalopathy>14 deaths

Intramuscular
injection
Additive (HCO-60)
Hopantenic acid

Symptoms

10,000 affected>14 deaths(* These are the Japanese figures; thalidomide is estimated to have caused birth defects in 6,000 children in West Germany and 500
children in the United Kingdom.)(Cited from Nihon Iyakuhin Sangyō Kindai-shi (Modern History of the Japanese Pharmaceutical Industry) p.130. Originally from Beppu
H., Hama R. & Murai N.: Nikkei Science. pp.20-21 (Dec. 1991).)

The strict safety standards pushed up the research anddevelopment costs for drug discovery and there were serious
risks in the industry. Later, with individual drug discovery
companies being unable to obtain sufficient data for assuring
human safety, they began to investigate the creation of acollaborative drug evaluation system, compiling safety datafrom candidate compounds no longer being developed anddrugs no longer being sold by other companies.
The drug discovery system involved more than evaluating
medicinal efficacy and synthesizing compounds; advanceswere also made in safety testing to ensure safety andmethods for evaluating pharmacokinetics. The framework ofmodern drug discovery was nearing completion in theJapanese drug discovery industry.
Completion of the Framework of Modern Drug
Discovery
Around this time, progress was being made in identifying
drug mechanisms and successive new drugs were being
produced using new mechanisms. Prompted by this, Japanesecompanies also started competing to discover new drugs.
As mentioned previously, the top-producing
pharmaceutical products in the 1960s were vitamins andantibiotics. The 1970s finally saw the emergence of drugs forthe central nervous system, circulatory system andsecond-generation antibiotics developed by drug companies
using their own drug discovery technologies (1, 3). According
to Takeda Nihyakunen-shi, the company history of Takeda
Pharmaceutical, the company’s pharmacology department
established specialized divisions for anticancer drugs in 1953
and for central nervous system drugs in 1954, followed by
the successive establishment of specialized divisions for
analgesic and anti-inflammatory drugs, endocrine system
drugs and digestive system drugs from 1961 to 1967. These
divisions worked on projects together with the chemical
synthesis group and the fermentation group, thus forming thebasis of the company’s research system (6). Safety researchcame a little later, as “the drug safety center was establishedin 1973, while the pharmacology department wasincorporated into the pharmacokinetics department in 1978,
forming the research system that is in place today”. Other
drug discovery companies started similarly organizing theirdepartments around the same time or slightly later.
Sections 3 and 4 of Chapter 2 above have outlined thehistory of drugs from the latter half of the 19th century
through to about the 1960s in terms of “The Origin ofModern Pharmaceutical Drug Discovery and Development”
and “From New Medicines to Improved Medicines andInnovative Medicines”. A review of the history of drug
development reveals that as the technologies of drug
discovery systems have grown more complete, drugs
discovery has advanced beyond the realm of easy,large-market initiatives with clear disease identification, as
shown below. Drugs in the following four areas haveemerged through drug discovery in the modern drug
discovery system.
(1) Antibiotics, antibacterials and other drugs for diseases
caused by external microbes(2) Drugs that act on the central or peripheral nervous
systems (including surgery-related drugs)(3) Digestive system drugs(4) Drugs for inflammation or allergies
Following on from these, “lifestyle-related diseases”
began gaining attention, with research and development
focusing on drugs such as:(5) Anti-hypertensives, diabetes medications, lipid-loweringdrugs, antithrombotic drugs and hyperuricemia drugs
Into the 21st century, genomic drug discovery andadvances in biotechnology drove progress in research anddevelopment into areas yet to be explored by the academic
world and (niche) areas with less demand. These drugs
included:(6) Niche-area drugs, cancer/immunity-related drugs anddrugs in areas currently lacking specific medicines
The “Detailed Discussion” in Chapter 4 outlines theresearch, development and marketing of drugs in Japan from

Systematized Survey on the History of Drug Discovery with Technical Development

37

after the war to the present day. The chapter opens with a
discussion on “drugs for lifestyle-related diseases”, namely,
anti-hypertensives, diabetes medications, lipid-loweringdrugs, antithrombotic drugs and hyperuricemia drugs, andexamines how outcomes have been achieved by postwar
Japanese drug discovery companies.
Detailed discussions on drugs for other diseases shall bepresented at another opportunity.

stimulation and then either metabolized by enzymes orreabsorbed by the storage granules and reused. This study

References[1] Matsushita A.: Folia pharmacologica Japonica 110 (5):277-295 (1997).

inactivation”.
While “adrenergic receptors” in the smooth muscle and[2] Tsunoda F.: Hekiso / Nihon Penishirin Monogatari (The
Story of the Japanese Penicillin – Hekiso). Shinchosha(1979).
[3] Nihon Iyakuhin Sangyō-shi (History of the JapanesePharmaceutical Industry): The Japanese Society for
History of Pharmacy (ed.) (1995).
[4] Imoto M.: The Chemical Society of Japan (ed.) Nihonno Kagaku 100-nen no Ayumi (100-year History ofChemistry in Japan). Kagaku Dojin (1999).
[5] Nihon Yakugakukai Hyakunenshi (100-year History of
the Pharmaceutical Society of Japan). The
Pharmaceutical Society of Japan (ed.) (1980).
[6] Takeda Nihyakunen-shi (200-year History of Takeda):
Takeda Pharmaceutical Co., Ltd. 200-203 (1984).
[7] Details on various products were made with reference tothe company histories of various drug discovery
companies.
2.4.2.
Completion of Modern Pharmacology
From 1940 to 1960, rapid developments were made inWestern pharmacology in relation to drugs for the central
nervous system, anti-inflammatory drugs, cardiovascular
drugs and digestive system drugs. The basic technologies andprocesses for new drug discovery and development werecomplete.
In 1946, Ulf Svante von Euler and Peter Holtz
demonstrated that noradrenaline acts as a neurotransmitter inthe mammalian sympathetic nervous system (1).
Using the explanation that adrenergic agonists
isoproterenol, adrenaline and noradrenaline act differently on
different tissues, Raymond Ahlquist hypothesized in 1948
that “the action of noradrenaline takes effect through two
different adrenergic receptors, α and β”. Interestingly, histheory was so unique that his first paper on it was not
accepted for publication in the authoritative American
publication Journal of Pharmacology and Experimental
Therapeutics (JPET).
Around the same time, Julius Axelrod contributed to thedevelopment of neurochemistry with his discovery of theprocess whereby noradrenaline stored at the ends of thesynapses is released from the storage granules by electrical38

laid the groundwork for later research on selective serotonin
reuptake inhibitors (SSRIs); Axelrod was awarded the Nobel
Prize in Physiology or Medicine in 1970, along with Ulf vonEuler (mentioned above) and Bernard Katz, for “theirdiscoveries concerning the humoral transmitters in the nerve
terminals and the mechanism for their storage, release andmyocardium were known receptors of catecholamines suchas adrenaline and noradrenaline, it was not until 1954 that
Raymond Ahlquist’s theory of α- and β-type adrenergic
receptors was accepted (3). This marked the beginning of atrend in research to split receptors into increasingly moredetailed categories, which continues to this day. Α-receptors
are characterized by causing vasoconstriction, thereby
increasing peripheral resistance and raising the bloodpressure. Β-receptors are further categorized into β1- andβ2-receptors; β1-receptor stimulation has been found to cause
heart excitation, while β2-receptor stimulation has beenfound to cause vasodilation and bronchodilation. Sir James
Whyte Black was the first to utilize this theory to synthesize
a receptor-specific compound and investigate its medicinal
efficacy (mentioned later).
Subsequent research has demonstrated that there areseveral subtypes of receptors. Initially, receptors werecategorized by agonist. Genetic cloning and the ability tosynthesize and utilize increasingly superior antagonists havemade it possible to identify further receptor subtypes andtheir molecular characteristics. For example, α-receptors are
categorized into α1- and α2-receptors; α1-receptors are further
categorized into α1A, α1B and α1D, while α2-receptors are
categorized into α2A, α2B and α2C (3, 4).
Currently, the action mechanisms of over 50% of drugs
can be explained as (i) mechanisms that either antagonize or
stimulate receptors or (ii) mechanisms that inhibit enzymes(see Chapter 3 for details).
The drug discovery process for creating receptor
antagonists was completed soon after the war. Examples ofuseful medications include β-blockers, H2 antagonists andcentral nervous system drugs, while anti-inflammatory drugs
are a good example of enzyme inhibitors.
References[1] U. S. von Euler: A Specific Sympathomimetic Ergone in
Adrenergic Nerve Fibers and its Relations to Adrenaline
and Noradrenaline. Acta Physiologica Scandinavica
12:73-97 (1946).
[2] Raymond Ahlquist: American Journal of Physiology
153:586-600 (1948).
[3] Raymond Ahlquist: Nature 214:597-598 (1967).
[4] Tanaka C. & Katō R.: New Yakurigaku (NewNational Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchPharmacology). Nankodo (1989).
2.4.3.
Discovery of β-Blockers and H2 Antagonists
James Black of Scotland was a professor at the Universityof Glasgow’s School of Veterinary Medicine. Hypothesizingthat antianginal drugs could eliminate oxygen deficiency inthe coronary vessels by controlling the action of the heart, hestarted working for British company ICI, where he engaged
in collaborative research with organic synthetic chemists todevelop the β-receptor blocker propranolol in 1965. At thetime, even the existence of β-receptors was only ahypothesis; however, this drug became widely used forangina and other conditions. The drug was developed using
the structure-activity relationship; Black obtained
propranolol by screening using techniques from the modern
drug discovery process.
Propranolol was the world’s first β-blocker (1). The idea
was that since noradrenaline released by the sympathetic
nervous system causes constriction by acting on the
β-receptors in the smooth muscle and myocardium, blocking
these receptors would regulate the heart’s pulse and inhibit
the constriction of the coronary arteries, causing them torelax. Although the use of propranolol initially proved very
effective against angina and other conditions, it was not yet
known at the time that different types of tissue have different
types of β-receptors. Since propranolol was a non-selective
β-blocker, it also blocked the β2-receptors in the bronchialsmooth muscle, causing side effects such as asthma.
Black then turned the focus of his research to studying H2
receptors. Although it was known at the time that histamines
promoted the secretion of gastric acid, histamine antagonists
had never been able to inhibit this secretion. (Early histamine
antagonists suppressed allergies by acting antagonistically on
H1-type histamine receptors, but did not act antagonisticallyon the H2-type receptors involved in gastric acid secretion.)
Black hypothesized that there were two types of histamine
receptors, H1 and H2, and set about developing the world’s
first H2 receptor antagonist. By screening H2 receptors, heobtained Nα-guanylhistamine, a partial histamine receptor
antagonist. Using this, he estimated the structure of H2
receptors and successfully developed burimamide, the firstgastric acid inhibitor. From burimamide, he went on todevelop the more effective metiamide, followed by thestronger, more effective and less toxic oral anti-ulcer drug
cimetidine (launched in the United Kingdom in 1976 by
SKF). Black achieved these research results at Smith, Kline& French Laboratories (SKF; now GlaxoSmithKline) (2). For
these achievements, Black was awarded the Nobel Prize inPhysiology or Medicine in 1988 (see Figure 2.8 for details on
Blacks achievements).
In Japan, many people had suffered from gastric ulcers
and duodenal ulcers from the Meiji Period onwards, Sōseki
Natsume among them; in many cases they proved fatal. The
use of H2 receptor antagonist cimetidine (developed in Japanby SKF and Fujisawa Pharmaceutical) from 1982 allowed
people to recover from these ulcers without surgery, which

was the usual method of treatment at the time.
Later, further advances were made in identifying thegastric acid secretion mechanism and the target shifted fromthe H2 receptors to the proton pump (Note 2), with ongoingcompetition over development. In Japan, the introduction ofH2 blocker famotidine by Yamanouchi Pharmaceutical andsecond-generation proton pump blocker lansoprazole byTakeda Pharmaceutical brought the medicinal treatment ofgastric ulcers and duodenal ulcers almost to completion, tothe alleviation of many patients. These drugs made asignificant contribution to identifying the causes of gastriculcers and duodenal ulcers.

Propranolol

Cimetidine

Histamine
AdrenalinBlack (UK) derived the β-blocker propranolol from the chemical structure ofadrenaline and then produced the antagonist cimetidine from histamine.
Propranolol provides relief to sufferers of angina, arrhythmia andhypertension; cimetidine was a ground-breaking new drug that meant surgery
was no longer required to treat ulcers.
Black was awarded the Nobel Prize in Physiology or Medicine.

Fig. 2.8β-Blockers and H2 Antagonists.

Note 1: Histamines, acetylcholine and gastrin act on their respective
receptors on the gastric wall; stimuli are transmitted by the proton
pump and gastric acid is secreted. Blocking the proton pump inhibits
the secretion of gastric acid regardless of the agonist.

References[1] Black JW, Crowther AF, Shanks RG, Smith LH,
Dornhorst AC: A new adrenergic beta-receptor
antagonist. The Lancet 283(7342): 1080-1081 (1964).
[2] Black JW, Duncan WAM, Durant CJ, Canellin CR,
Parsons EM: Definition and antagonism of histamine
H2-receptors. Nature 236:385-390 (1972).

Systematized Survey on the History of Drug Discovery with Technical Development

39

2.4.4.

Anti-Inflammatories (from Aspirin to Selective
Cyclooxygenase II Inhibitors)
Anti-inflammatories started with quinine and salicylic
acid from crude drugs. Chinchona, a crude drug from SouthAmerica, is believed to have been brought to Europe in 1630.
Chinchona became known as a specific medicine against
malaria, for which there was no medicine at all at the time. It
was also found to have a strong analgesic-antipyretic effect.
Quinine, the main component in chinchona, was extracted
in 1820 by French chemists Pierre-Joseph Pelletier andJoseph Bienaimé Caventou; the French went wild withenthusiasm at their discovery and the country gave theseyoung scientists the unprecedented honor of erecting acommemorative monument to them. The French Académiedes Sciences is said to have received donations from all over
the world when it erected the statue of the two men on theboulevard St.-Michel in Paris. The statue was destroyed by
the Germans in the Second World War, but a replacement
was erected in the same location after the war (9).
Quinine was in such demand for its powerful antimalarial
effect that research began on large-scale synthesis of it assoon as it was extracted. During the course of its synthesis,
pyrazolone derivatives began to be synthesized. These

pyrazolone derivatives were found to have a powerfulanalgesic-antipyretic effect; antipyrine (Ludwich Knorr,
1883) and sulpyrine were synthesized from these.
The analgesic-antipyretic effect of these pyrazolone
derivatives is now believed to work through the central
nervous system. These drugs were found to cause an eruption
known as antipyrine exanthema on rare occasions; in severecases, they were also found to cause leucopenia.
Nevertheless, the pyrazolone structure was later used as thebasic structure for anti-inflammatory drugs. In 1949,
phenylbutazone was released on the market as ananti-inflammatory with fewer side effects. Phenylbutazone
was characterized for having an analgesic-antipyretic effectas well as an anti-inflammatory effect.
In 1897, acetylsalicylic acid (aspirin) was synthesizedfrom salicylic acid. It had powerful, clinically-provenanalgesic, antipyretic and anti-inflammatory effects. Its
mechanism of action was further clarified in the 1960s; it
was found to demonstrate its anti-inflammatory effect byinhibiting cyclooxygenase (COX), the first enzyme in thearachidonate cascade, thereby suppressing the production ofvarious inflammation-related prostaglandins (see Figure 2.9)
(1).

Phospholipid of cell
membrane

PG: Prostaglandin
LT: Leukotriene
TX: Thromboxane
COX: cyclooxygenase

Phospholipase A2

Arachidonic acid

PGI2 synthase

5-Lipoxygenase

PGE2 synthase
TXA2 synthase
Neutrophil
migration effectAlso called‘prostacyclin’
Platelet aggregation
inhibiting effectVascular smoothmuscle relaxant effect
Gastric acid secretion
inhibiting effect, etc.

Act as apotentiator of
inflammation
Increases fever,pain and otherinflammation at
the inflammation
site

Fig. 2.940Plateletaggregation effectVascular smoothmuscle contraction
effectBronchial smoothmuscle contraction
effectVascular smooth muscle
contraction
Increased vascular permeability
Eosinophil migration effectBronchial smooth muscle
contraction

The Arachidonate Cascade.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchJohn Vane was awarded the Nobel Prize in Physiology or
Medicine for this research. Aspirin was later found to have a

Aspirinplatelet aggregation inhibiting effect and a uricosuric effect.
As its field of application has expanded, it has become
regarded as one of the drugs that have made the greatest
contribution to medical treatment in the history of humanity.
Although antipyrine and sulpyrine similarly end in

An antipyretic-analgesic derived fromsalicylic acid extracted from willow.
Recently demonstrated effectiveness as anantithrombotic. One of the mostoutstanding drugs produced by humanity.

“pirin/pyrine”, their analgesic-antipyretic effects act on thecentral nervous system and they are not classified as
nonsteroidal anti-inflammatory drugs (NSAIDs), which havea COX-inhibiting anti-inflammatory effect.
Indomethaci

Indomethacin was researched and developed by Merckand gained some attention as a new pharmaceutical

A COX-1 inhibitor with demonstrated
complete recovery in animal models andpowerful effectiveness in human patients.
Many different varieties of anti-inflammatories
called NSAIDs produced from it.

substance that demonstrated an extraordinarily powerfulanti-inflammatory effect in animal models. Its powerfulanti-inflammatory and analgesic effects were confirmed
clinically and it was launched in the United States in 1963.
Fierce development competition ensued, with various other

Celecoxib

phenylpropionic acid and phenylacetic acid derivatives
synthesized using this structure as the lead compound.
Since these differed in structure from corticosteroids,
which have a powerful anti-inflammatory effect, they werelabelled as acidic anti-inflammatories in the nonsteroidal
anti-inflammatory drug (NSAID) category(2)

COX-2 selective inhibitor.
Dramatically reduced side effects in thealimentary canal, but long-term trials haveshown adverse effects in the cardiac system.

. Whileprolonged use of steroids causes a number of side effects,
including gastrointestinal ulcers, suppression of immunity,
causing susceptibility to infection, and greater susceptibility

Fig. 2.10 Typical NSAIDs.

to osteoporosis, diabetes and hypertension, these side effects
are unlikely from nonsteroidal drugs.

However, it was eventually found that acidic

Hisao Yamamoto of Sumitomo Chemical investigation
methods for synthesizing indomethacin and came up with a
new method of synthesizing it by directly closing

With the Japanese tending to be more susceptible togastrointestinal disorders, Japanese drug discovery

acylphenylhydrazine into an indole ring, which wascompanies embarked on developing anti-inflammatories withdifferent chemical structures from thepreviously said to be impossible. This method made it
possible to supply a higher-yield, higher-purity product;
Sumitomo Chemical licensed the technology back to Merck.
In 1967, Sumitomo Chemical started marketing it as an
inflammation suppressant for rheumatism (3).
The age of importing anti-inflammatories continued inJapan. After indomethacin in 1996 came mefenamic acid,followed by flufenac and ibufenac in 1967, ibuprofen in
1971, diclofenac in 1974, ketoprofen, flurbiprofen andnaproxen in 1978 and piroxicam in 1982. On thedomestically-produced NSAID market, Sankyo launchedloxoprofen in 1986 (4).

anti-inflammatories damage the gastric mucosa and cause
other side effects in proportion to their medicinal efficacy.

phenylacetic/phenylpropionic acid-based acidic
anti-inflammatories. This resulted in the creation of
successive domestically-produced non-acidic NSAIDs.
Daiichi Pharmaceutical launched epirizole in 1970, while
Takeda Pharmaceutical launched difenamizole in 1973,
Fujisawa launched tiaramide in 1974, Shionogi launchedperisoxal in 1978 and Yoshitomi Pharmaceutical launchedpranoprofen in 1981. These were known as basicanti-inflammatories; while they had milder gastrointestinalside effects, they were not as powerful as their acidic
counterparts in terms of the main anti-inflammatory effect (3,4, 6).
Acidic anti-inflammatories were essentially used tosuppress pain at sites of inflammation stemming fromrheumatism or osteoarthritis and did not treat the root causeof the disease. Proper anti-rheumatic drugs did not appear
until the emergence of low-molecular-weight drugs andSystematized Survey on the History of Drug Discovery with Technical Development

41

42

antibody drugs that acted on the immune system. However,dosages were kept low in Japan to reduce the side effects ofStudies began on COX-2 specific inhibitors in order toimprove these side effects. In 1992, Pfizer marketed the firstacidic anti-inflammatories; sales of these drugs increased asthey started being used to relieve colds and muscular pain.

coxib-type (Note 2) selective COX-2 inhibitor celecoxib(produced by Searle). This reduced the side effects in the

When tissue is severely damage, blood vessels at the areaof inflammation expand and the blood flow increases,

gastrointestinal system, as expected, and triggered a global
development boom in COX-2 inhibitors. Celecoxib wasleaking blood cells from the blood vessels into the tissue.
Leukocytes, macrophages and mastocytes infiltrate thelaunched on the market in Japan in 2007 by Yamanouchi
Pharmaceutical and Pfizer as an anti-inflammatory andinflamed tissue and the inflammation progresses. Damaged
and inflammatory cells in the inflamed tissue release algesic

analgesic for rheumatoid arthritis and osteoarthritis.
However, none of the inhibitors were perfectly selective

substances with vascular hyperpermeability effects, such as
bradykinin, thromboxane, leukotriene, serotonin andbetween COX-1 and COX-2; the actual efficacy and side
effects were determined by the balance between COX-1 andhistamine, as well as algesic potentiators, such as
prostaglandin. Bradykinin and other algesic substancesCOX-2 and differed not only due to enzyme selectivity, butalso due to tissue affinity. Thus, development competition

characteristically produce pain by directly stimulating thereceptors, while algesic potentiators, such as prostaglandin E

continued over various anti-inflammatory drugs.
It was later reported that COX-2 is activated in cancer(PGE2) and prostacyclin (PGI2), characteristically increase
receptor reactivity. Prostaglandins and leukotrienes

tissue (6), with other theories emerging to say that it promotes
the activation of cancer. With Merck guaranteeing its(generically called prostanoids) are produced from thearachidonate cascade and play an important role inanti-inflammatory effect and safety, rofecoxib (Merck: US
brand name Vioxx®; unapproved in Japan) was widely

inflammation.
Phospholipase A2 is activated by the cells in the inflamed

adopted; a clinical study began on its use for the secondary
prevention of bowel cancer.

tissue. The phospholipids in the cell membrane releasearachidonic acid, activating cyclooxygenase (Note 2) II

However, the study revealed an unforeseen issue:
increased risk of thrombosis or cardiovascular complications(inducible enzyme COX-2), which converts the arachidonic
acid into prostaglandin H2 via prostaglandin G2. The

such as heart attacks. Rofecoxib was voluntarily recalled in
2004. Many side effects victims and their families tookproduction of prostaglandins and thromboxanes (both are
termed as prostanoids), which are inflammation-related

Merck to court; the company eventually ended up paying out$4.85 billion (Note 3).

substances, aggravates the inflammation; however,suppressing the COX-2 also suppresses the production of

While it is not yet known whether the increased risk ofcardiovascular events is common to all coxib drugs, reported

inflammatory factors downstream (see Figure 2.9).
Meanwhile, constitutive enzyme COX-1 is expressed byresearch results suggest a low correlation between celecoxib(Pfizer) and cardiovascular complications (7).

the stomach, platelets, kidneys and almost all other tissues; inthe gastric wall, it produces prostacyclin, which protects the

COX-2 inhibitors suppress the production of prostanoids
and suppress the production of PGI2 in vascular endothelial

gastric wall. It also works to maintain blood pressure andcirculation in the kidneys.

cells. However, they do not suppress the production ofthromboxane A2, which promotes platelet aggregation; someFor example, COX-1 is constantly expressed by theplatelets; it has been reported that the platelet-inhibiting

theories consider this to be a cause of cardiovasculardisorders. Figure 2.10 shows the chemical structures ofeffect of aspirin is achieved by inhibiting COX-1. Since
aspirin has a platelet-aggregation-inhibiting effect at small

typical anti-inflammatories aspirin, indomethacin andcelecoxib.

doses, it has come to be widely used around the world toprevent the recurrence of cerebral infarction (see Section 4.4,

Note 1: Cyclooxygenase (COX) is an enzyme involved in the

Medications for Thrombosis and Clotting Disorders).
The use of aspirin and indomethacin, which have little

start of the arachidonate cascade. Arachidonic acid isoxidized by cyclooxygenase into PGG and PGH, from which

enzyme selectivity, has occasionally resulted in serious
gastric ulcers as a side effect. In particular, it has caused

various prostanoids are biosynthesized. COX exists in two
forms, I and II.

gastric perforation when used by sufferers of severerheumatism. Side effects of anti-inflammatory drugs were

Note 2: A classification name for new drugs withthe third leading cause of death among rheumatism patientsin the United States in 1997 (5:120-121).

three-dimensional structures designed to achieve COX-2
selectivity.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchNote 3: The findings of the clinical study were published in 2005
after the study was terminated. The trial targeted people within 12
weeks of having had surgery for colorectal cancer. Subjects weredivided into a rofecoxib group and a placebo group, 1300 in each,and administered their respective treatments for three weeks. Afterthe trial, 1074 subjects and 1092 subjects from the two groups
respectively participated in the study. The combined number ofsubjects who either died or suffered non-fatal cardiovascular eventswas 59 in the rofecoxib group and 34 in the placebo group in 32 and20 events respectively occurring after the study (8).

2.4.5.
Central Nervous System Agonists
Illnesses treated with central/peripheral nerve agonists
include schizophrenia, anxiety, nervous disorders, depression
and other mental disorders, as well as dementia, epilepsy,
Parkinson’s disease and other illnesses caused by thedegeneration of nerve cells. The drugs used to treat
schizophrenia, depression, nervous disorders and anxiety arecalled psychotropic drugs. There is a wide range of nerve
agonists in addition to these, including general and local
anesthetics used for surgery and analgesics. All around theworld since ancient times, many of the crude drugs used

References[1] John Vane: Inhibition of prostaglandin synthesis as amechanism of action for aspirin-like drugs. Nature New
biology 231(25): 232-235 (1971).
[2] Hart F, Boardman: Anti-inflammatory Agent,
Indomethacin. A New Non-steroid. British Medical
Journal 2(5363): 965-970 (1963).
[3] Sumitomo Seiyaku 20-nen-shi (20-year History of
Sumitomo Pharmaceutical): Sumitomo Pharmaceuticals
Co., Ltd. 16-17 (2005).
[4] Matsushita A.: Folia pharmacologica Japonica 110 (5):277-295 (1997).
[5] Morita I., Mizushima Y. (eds.): NSAID no Tsukaikata
Kotsu to Otoshiana (How to Use NSAID: Tips andPitfalls). Nakayama Shoten 120-121 (2006).
[6] Watson AJ: Chemopreventive effects of NSAIDs against
colorectal cancer: Regulation of apoptosis and mitosis
by COX-1 and COX-2. Histology and Histopathology.
13:591-597 (1998).
[7] Graham DJ, Campen D, Hui R, et al.: Risk of acute
myocardial infarction and sudden cardiac death inpatients treated with cyclo-oxygenase2 selective andnon-selective non-steroidal anti-inﬂammatory drugs:
nested case-control study. Lancet 365:475-448 (2005).
[8] Robert S. Bresalier, Robert S. Sandler, John A. Baron,
et al.: Cardiovascular Events Associated with Rofecoxib
in a Colorectal Adenoma Chemoprevention Trial. New
England Journal of Medicine 352:1092-1102 (2005).
[9] Taylor N., Nanba T. & Nanba Y. (trans.): Sekai wo
Kaeta Yakuyō Shokubutsu (Plant Drugs that Changed
the World). Sogensha (1972).
[10] Details on various products were made with reference tothe drug interview forms from various companies.

alongside witchcraft had strong effects on the mind andnerves; modern research on the alkaloids extracted fromthese crude drugs has contributed to advances inneuropharmacology.
Drugs for Schizophrenia
The belief that people suffering from mental illnesses arepossessed by evil spirits has persisted throughout thecenturies since ancient times. To cure the disease, it was
believed necessary to drive out the evil spirits; extreme
treatment methods existed through to early modern times andincluded drilling into the skull or locking patients in adungeon.
Trialing various different drugs began in the 20th century
and included alcohol, chloral hydrate, opium and alkaloids. It
was found that administering these to patients in highconcentrations could eliminate patient anxiety and induce
calm and drowsiness, but could not alleviate hallucinations
or other mental disorders. Around this time, radical treatment
therapies such as lobotomy (partial surgical removal of thefrontal lobe) and electroconvulsive therapy were also being
used.
Chlorpromazine was the first antipsychotic drug to be
used for diseases affecting the central nervous system. While
researching anesthetics for surgery patients, French surgeon
Henri Laborit found that antihistamines were effective foralleviating patient fear and anxiety. Based on these findings,
the phenothiazine derivative chlorpromazine was discoveredat the Rhône-Poulenc laboratory in 1952 by screening
peripheral compounds (1). In 1952, French psychiatrists Jean
Delay and Pierre Deniker administered chlorpromazine toschizophrenia patients and found that it had a therapeutic
effect of suppressing patient stimulation and reducing
hallucinations. The drug was introduced to Japan in 1955.
This new drug demonstrated dramatic effects on
schizophrenia patients, heralding the arrival of a new era inmental illness treatment. Stories began to emerge of the drug
being administered to patients who had previously stoodmotionless week after week in the same place in the hospital,or patients who had previously been so violent they had to be
restrained, but now no longer needed supervision (2). It was
truly epoch-making.

Systematized Survey on the History of Drug Discovery with Technical Development43

It consequently became possible to control mental

receptors. It was also found that noradrenaline is a central

illnesses with medication, thus putting a stop to the previous

nervous system transmitter involved in anxiety andtreatments of electroconvulsive therapy, insulin stimulation

restlessness and that it is helpful to block the adrenergic α

and lobotomy. Most patients no longer needed to be kept inreceptors. The idea came to the fore that treatment drugs forconfinement, thus reducing the hospitalization rate ofschizophrenia should regulate the balance of various

schizophrenia patients worldwide.

neurotransmitters rather than selectively antagonizing the D2

Unlike previous hypnotic sedatives, this drug was a major

receptors.

tranquilizer; many other phenothiazine-based antipsychotic

Clozapine, marketed overseas in 1969, demonstrated a D2

drugs were later developed using chlorpromazine as the leadantagonist effect as well as 5-HT2 and α1 blocking effects. It

compound. In 1958, a compound synthesized in the process

also acted on the histamine H1 and muscarinic receptors.

of developing an antidiarrheal drug was found to have a

Researchers found that the main action could be separated

strong antipsychotic effect; the compound was haloperidol.

from the side effects; this drug served as the basic model for

Haloperidol has stronger hallucination and delusion

developing next-generation atypical antipsychotic drugs.
It was eventually found that dopamine has presynaptic

suppressing effect than chlorpromazine and is also
fast-working; it has consequently been used as a lead

(Note 2)compound in the development of butyrophenone-based

This made it possible to develop drugs that act on both the

antipsychotic drugs.

dopamine receptors and the serotonin receptors.
Risperidone was introduced to Japan in 1996 as a

In 1963, pharmacological research revealed that thesedrugs act on the dopaminergic neurons to block the
dopamine receptors(Note 1)

. Blocking the dopamine D2

serotonin receptors that inhibit the release of dopamine.

serotonin dopamine antagonist (SDA), effective against both
negative and positive symptoms. Perospirone was also

receptors in the nigrostriatal pathway in the midbrain is

introduced to Japan a little later than risperidone. Unlike thebelieved to be the most significant effect in schizophrenia

conventional antipsychotic drugs, these affected thetreatment. Drugs were screened in vitro and in vivo toneurotransmitters, which made them effective against

determine the strength of the D2 receptor blocking; a good

negative symptoms. The extrapyramidal symptoms arecorrelation was found between the dopamine receptor

surmised to be suppressed by the serotonin inhibiting action.

binding capacity and the clinical dosage.
However, while these antipsychotic drugs worked well for

This was followed by the development of quetiapine andolanzapine. Known as multi-acting receptor targeted

suppressing positive symptoms, strong side effects

antipsychotics (MARTA), these acted on various different(extrapyramidal symptoms) similar to the symptoms ofneural receptors. These became known as second-generation

Parkinson’s disease occurred in proportion to the receptor(atypical) antipsychotics, as opposed to the existing (typical)

binding capacity, including shaking (tremors) or rigidity of

antipsychotics (3, 4).
Aripiprazole, developed by Ostuka Pharmaceutical in

the hands and feet, immobilization or difficulty in movement
and feelings of restlessness.
Also, although the drugs were effective against
hallucinations, delusions and other positive symptoms (the2006, is a classic example of a domestically-produced,
second-generation drug. Since it has a partial dopamine D2
agonist effect, it has the pharmacological properties of acting

manifestation of phenomena that are not normally present),

as a dopamine D2 antagonist when the dopaminergic nerves

they had hardly any effect against social withdrawal, loss ofare overactive and as a dopamine D2 agonist whenmotivation and other negative symptoms (the loss of

dopaminergic neurotransmission is low; it is known as aphenomena that are normally present when healthy).

dopamine system stabilizer (DSS). Aripiprazole also has a

These first-generation drugs are known as typicalpartial agonist effect on serotonin receptor 5-HT1A and an

antipsychotics and were successively produced withantagonistic effect on serotonin receptor 5-HT2A. Due todopamine antagonism as the indicator. However, it has notthese pharmacological properties, aripiprazole has been

been possible to separate the antipsychotic effect from thereported to be effective for schizophrenia with few

extrapyramidal side effects.
Research findings showed that not only is chlorpromazine

extrapyramidal symptoms and no increase in prolactin levels(5).

a selective dopamine antagonist, it also has a wide range ofside effects, including blocking histamine receptors,
serotonin receptors, muscarinic receptors and adrenergic α144National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

In 2008, Dainippon Sumitomo Pharma developed
blonanserin, a second-generation antipsychotic with a new

his invention of “site-directed mutagenesis of DNA”. And
with the son of Albert Einstein also having schizophrenia,

structure that has a dopamine D2 receptor blocking effect anda serotonin 5-HT2 receptor blocking effect with few

could it be that there is an inherited pattern in the nervous
system that may lead to a major creative discovery or to a

extrapyramidal symptoms (6).
Although ongoing research and development for new

major thinking disorder? Consider the mathematician John
Nash who developed schizophrenia after he did the work thatdrugs with new mechanisms of action is still ongoing, theroot cause of schizophrenia still remains unsolved. Figure

led to his Nobel award.”

2.11 shows the chemical structures of some representative
examples of typical and atypical antipsychotics.

AntidepressantsMonoaminergic nerves (Note 3) are known to be involved instimulating overall brain function (see Figure 2.12).

In “Psychosis: Discovery of the Antipsychotic Receptor”,
Neil Seeman states the following (7:172-178).
“In May 1997 James Watson came to Toronto to give theAndrzej Jus lecture on Neuroscience and Ethics…
At lunch that day Watson said that there were no new
ideas in schizophrenia research and that we would all have to
wait until the human genome was sequenced…. The humangenome has now been sequenced and known for about ten
years, but there are no new dramatic breakthroughs in this
aspect of DNA research on schizophrenia. In fact, since 1999,
there are approximately 50 to 100 genes announced eachyear as being linked or associated with schizophrenia, but
none have stood the test of time in being readily replicatedbeyond any doubt, and none have stood the test of time as abiomarker for schizophrenia… At lunch that day, it became
clear that Watson’s intense interest in schizophrenia waspresumably related to the fact that his son had schizophrenia.
And this brings to mind that the son of Dr. Michael Smith

While reserpine was historically used as ananti-hypertensive, American scientist Nathan Kline used it totreat schizophrenia in 1954. However, it was found that theadministration of reserpine caused depression-like symptoms.
It was later discovered that reserpine has a synaptic vesicle
draining effect on dopamine, noradrenaline and otherneurotransmitters; it was hypothesized that the lowering of
the catecholamine levels in the brain was the mechanism thatcauses depression.
It was noted that patients administered with iproniazid, a
tuberculosis drug developed in 1951, would become lively.
Investigation into the cause of this revealed that iproniazid
has a powerful inhibitory effect on monoamine oxidase(MAO: an enzyme that intraneurally oxidizes and degrades
monoamines); it was presumed that inhibiting thedegradation of catecholamines induces a state of excitement.

also had schizophrenia. Smith received the Nobel Prize for
Chlorpromazine

Haloperidol
Point of origin of antipsychotics: Rhône-Poulenc
Manufacturing method patented in Japan by
Yoshitomi Pharmaceutical: 1955

Risperidone

Classic first-generation; powerful D2
antagonistic action
Strong side effects: Rhône-Poulenc

Olanzapine

Second-generation:
serotonin/dopamine antagonistic
actionSecond-generation: representative
example MARTA
Eli Lilly & Co.

Aripiprazole
Blonanserin

Second-generation: dopamine
system stabilizer (DSS)
Domestically produced: Ostuka
Pharmaceutical

Second-generation
Dopamine / serotonin antagonistic
actionDomestically produced: Dainippon
Sumitomo Pharma

Fig. 2.11 Chemical Structural Formulas of Representative Examples of Antipsychotic Drugs.

Systematized Survey on the History of Drug Discovery with Technical Development

45

In 1958, a clinical trial of the antipsychotic imipramine
revealed that it had an antidepressant effect. Imipramine wasconjectured to demonstrate this effect by suppressing thereuptake of monoamine neurotransmitters into the nerves,
thereby increasing the amount of monoamines in the synaptic
cleft; it was theorized that lowering the monoamine levels
would produce depression. Imipramine was introduced toJapan in 1959.
These were first-generation (conventional) antidepressants.
Since imipramine and amitriptyline have tricyclic structures,
they became known as tricyclic antidepressants. In 1956,
Joseph Schildkraut of the US National Institute of Mental
Health proposed the hypothesis that depression reduces the

Nevertheless, many aspects of the mechanisms that cause
depression are yet unknown; future progress can be expected
in new drug development and the identification of
mechanisms.
Although monoamine oxidase inhibitors (MAOIs) havealso been effective, they have fallen out of use as improved
monoamine reuptake inhibitors have emerged, as inhibiting
monoamine oxidase also affects other tissues and organs.
More recently, antidepressants have started being
administered not only for depression, but also for neurosis
and schizophrenia. Figure 2.12 shows the chemical structuresof some representative examples of first- andsecond-generation antidepressants.

noradrenaline levels in the brain and that antidepressants
Tricyclic antidepressantfirst-generation

restore those noradrenaline levels. The improved tricyclic
antidepressants and tetracyclic antidepressants that later
emerged are sometimes referred to as second-generation
antidepressants (4).

ImipramineFirst used as anantidepressant. Powerful
effect, but strong side
effects as wellAmitriptyline

However, it was later suggested that serotonin reflects amore pathological condition in the brain of people suffering
Antidepressant,new-generationfrom depression; research began on selective serotonin
reuptake inhibitors (SSRIs). These are also called
next-generation antidepressants.
Since the first-generation antidepressants were notspecific monoamine reuptake inhibitors, they had various
side effects, including anticholinergic effects and adrenaline

Milnacipran
Serotonin noradrenaline
reuptake inhibitor (SNRI)

Paroxetine
Selective serotonin
reuptake inhibitor (SSRI)

α1 blocking effects. The new-generation drugs, however,Fig. 2.12 Representative Examples ofwere specific to the serotonergic nerves; the mechanism of

Antidepressants.

action and the side effects were vastly different from those of
the conventional drugs (2).
In our complex and advanced modern society, there has
been an increase in the number of people showing signs ofdepression. Successive (i) selective serotonin reuptake
inhibitors (SSRIs) and (ii) serotonin noradrenaline reuptake
inhibitors (SNRIs) were developed in the West; many ofthem were introduced to Japan. The former (i) includes
fluvoxamine (launched in 1999, developed by Meiji Seika
Pharma), paroxetine (launched in 2000, developed by
GlaxoSmithKline; Japan’s first depression and panic disorderdrug) and sertraline (launched in 2006, developed by Pfizer),
while the latter (ii) includes milnacipran (launched in 2008,
developed by Asahi Kasei Pharma and produced by Pierre
Fabre Medicament; Japan’s first SNRI) and duloxetine(launched in 2010, Eli Lilly Japan). All of these wereintroduced products marketed in Japan. Fluoxetine by Eli
Lilly & Co. is widely used around the world, but has not yet
been approved in Japan.
The reason that Japan has not produced any
antidepressants can be surmised to be due to the low demand

Antiparkinsonians
Parkinson’s disease is a neurodegenerative disease withcardinal signs of muscular rigidity, tremors andimmobilization. In 1919, it was confirmed thatneurodegeneration and neuronal loss occur in the substantia
nigra within the brain of people suffering from Parkinson’s
disease. The substantia nigra produces dopamine, theneurotransmitter for the dopaminergic neurons and it isthought that degeneration in this region causes degradation in
dopaminergic nerve function. With the pathogenic
mechanism identified, theoretical discussion began on a drug
remedy.
Activation of the dopaminergic neurons was essential.
Means proposed to achieve this included: (i) increasing the
dopamine levels; (ii) inhibiting the metabolic enzymes(catechol-O-methyl transferase [COMT] or monoamineoxidase [MAO]) involved in dopamine degradation; and (iii)
reducing the acetylcholine levels in an effort to raise theactivity of the dopaminergic neurons through negative
feedback.

for these drugs, as the culture in Japan has always been tohide depression and other mental illnesses.

46

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchDOPA (L-3,4-dihydroxyphenylalanine) acts as aneurotransmitter in the brain as it is decarbonized by DOPA-

Central stimulants
In 1885, Nagayoshi Nagai successfully extracted

decarboxylase to become dopamine. However, if this isadministered externally, the dopamine cannot pass throughephedrine from ephedra herb; amphetamine was synthesizedfrom ephedrine in Germany in 1887; Nagayoshi Nagai andthe blood-brain barrier (Note 4), although the DOPA can.
Accordingly, a method was devised whereby DOPA

Kinnosuke Miura synthesized methamphetamine in 1893.
Amphetamine hit the American market in 1933 as theadministered orally migrates to the brain and is converted to
dopamine by the action of the DOPA- decarboxylase in theinhaled asthma drug Benzedrine®. Many people used it as acough medicine, although it started being abused whenbrain, thereby supplementing the dopamine deficiency (Note 5).
A dopamine formulation (DOPA®) applied clinically in 1967

people began to discover the amphetamine stimulant effect.
Some companies marketed it as a diet drug, as it also had an

by George Cotzias was long used as the main drug treatment
for Parkinson’s disease. By 1980, it was being used in aappetite-suppressing effect. With news of such abuse, the US
Food and Drug Administration (FDA) started restricting thecompound formulation combined with a dopamine
decarboxylase inhibitor.

prescription of it in 1959.
Methamphetamine, which has far stronger effects than

Later, dopaminergic agonist ergot alkaloids were used; theergot alkaloid bromocriptine was marketed by Sandoz

amphetamine, was launched on the German market in 1938,
but its harmful effects were soon realized and it was

Pharmaceuticals in 1979. Ergot alkaloid derivative pergolide
mesylate was released by Pfizer in 1994. Non-ergot

designated as a dangerous drug by the German authorities in1941.

derivatives were also developed, having different structuresfrom ergot alkaloids. Doktor Karl Thomae launched

In Japan, Takeda Pharmaceutical marketed anamphetamine formulation under the brand name Zedrin® intalipexole hydrochloride in 1996, while Nippon Boehringer
launched pramipexole in 2004. In 2006, GlaxoSmithKline

1941, while Dainippon Pharmaceutical marketed amethamphetamine formulation under the brand namereleased ropinirole in 2006.
CMOT and MAO inhibitors have also been used. In recent

Philopon®. During the Second World War, the Japanesemilitary distributed these pills to munitions factory workers

years, these have shown to be effective in extending the life
expectancy of patients with Parkinson’s disease to be on par

to increase productivity; they were also distributed tosoldiers and crew members on night fighters. After the war,with the average lifespan.
However, Japanese companies have made few

these drugs were readily obtainable at drugstores and on theblack market; the social issue of increasing drug abuse led todevelopments in this field; most of these drugs are imported
from overseas.

the enactment of the Stimulants Control Act in 1951 (8).

Catecholamine

Histamine

Serotonin
Tryptophan

Histidine

Tyrosine
Tryptophan hydroxylase

Tyrosine hydroxylase

5-Hydroxytryptophan
Histidine decarboxylase

Amino aciddecarboxylase

Serotonin

Aromatic amino aciddecarboxylase

Histamine
Dopamine
Dopamine β-hydroxylase

Adrenaline

Noradrenaline

Monoamineneurotransmitters arebiosynthesized from aminoacids.
* indicates neurotransmitters.

Phenylethanolamine
N-methyltransferase

Fig. 2.13 Monoamine Neurotransmitter Biosynthesis Pathways.

Systematized Survey on the History of Drug Discovery with Technical Development

47

Stimulants have been used as reagents in pharmacologicalexperiments to identify pathogenic mechanisms of various
mental disorders. Research on mechanisms of action has
confirmed that amphetamine forces the release of
neurotransmitters noradrenaline and adrenaline from thesynaptic vesicles.
Refer to Figure 2.13 for a summary of the biosynthesis ofcentral nervous system agonists (in vivo agonists).
The above has provided a simplified overview of the
postwar research and development of some central nervous
system drugs; however, there are many more besides these.
Further details on central nervous systems drug await anotheropportunity.
Note 1: Dopamine is a neurotransmitter with a vital role to play inthe central nervous system; it is not simply a precursor tonoradrenaline. Arvid Carlsson, Eric Kandel and Paul Greengard
were jointly awarded the Nobel Prize in Physiology or Medicine in2000 for “their discoveries concerning signal transduction in the
nervous system”.
Note 2: A synapse is a point of connection between neurons andother cell types (nerve cells and muscle cells) and contains a gap ofaround 20nm. Cells on the transmitting side of the electrical stimulus
are presynaptic; cells on the receiving side are postsynaptic. Moredetails are given in Figures 2.4 and 2.6.
Note 3: Monoamines include serotonin, noradrenaline, adrenaline,
histamine and dopamine. Of these, noradrenaline, adrenaline anddopamine contain catechol groups and are referred to as
catecholamines.
Note 4: The blood-brain barrier is a barrier between the brain and theblood. The gap between the endothelial cells in the blood isextremely narrow in the brain and only a few substances, such as
glucose, are able to pass through. The blood vessels are alsosurrounded by glial cells; this also restricts substances from passing
through.
Note 5: When DOPA is administered for Parkinson’s disease,patients are advised to avoid excessive consumption of foods rich invitamin B6. This is because vitamin B6 is a coenzyme of DOPA
decarboxylase; high amounts of vitamin B6 will activate the enzyme.
When the DOPA metabolizes into dopamine in the blood, it will not
be able to pass through the blood-brain barrier, thereby losing theeffectiveness.

References[1] Shook R., Kobayashi T. (trans.): Shinyaku Tanjō(Miracle Medicines). Diamond 50-59 (2008).
[2] Kudō Y.: Shinkei Yakuri-Gaku Nyūmon (Introduction to
Neuropharmacology). Asakura Publishing (2003).
[3] Unezaki S., Takeuchi H.: Seishin/Shinkei Shikkan no
Yakubutsu Chiryō (Medication for Mental and
Neurological Disorders). Ohmsha (2012).
[4] Himei A.: Seishinka no Kusuri ga Wakaru Hon (Book to
Understand Psychiatric Medicine) (2nd edition).
Igaku-Shoin (2011).
[5] Iyakuhin Intabyū Fōmu (Drug interview form).
Aripiprazole. Otsuka Pharmaceutical Co., Ltd. (Jan.
2014) (15th revision).
[6] Iyakuhin Intabyū Fōmu (Drug interview form).
Blonanserin. Sumitomo Dainippon Pharma Co., Ltd.
(Mar. 2012) (7th revision).

48[7] Seeman N., Seeman P., Watanabe M.: Kō
Seishinbyō-yaku Juyō-tai no Hakken Monogatari(Psychosis: Discovery of the Antipsychotic Receptor).
Seiwa Shoten (2011).
[8] The Pharmaceutical Society of Japan (ed.): Nihon
Yakugakukai Hyakunenshi (100-year History of thePharmaceutical Society of Japan). (1980).

2.4.6.
Advances in Bioscience and Drug Discovery
While the term biotechnology is a combination of thewords “biology” and “technology”, this is not exactly how it
is defined. Accordingly, in this paper, the term
“biotechnology” is used to refer to technology that chiefly
comprises gene recombination technology and encompasses
cell fusion technology and cell/tissue culturing technology,
while the term “biopharmaceuticals” is used to refer topolymeric drugs produced using this technology.
The origins of biotechnology in this sense can be traced
back to 1953, with the discovery of the complementary
double-stranded, double helix structure DNA model by
American biologist James Dewey Watson and British
physicist Francis Harry Compton Crick. This double helix is
said to have been the greatest discovery of the century forunravelling the secrets of life. Watson and Crick wereawarded the Nobel Prize in Physiology or Medicine in 1962.
In 1972, Paul Berg (awarded the Nobel Prize in Chemistryin 1980) of Stanford University succeeded in splicing
monkey virus DNA (SV40) with Escherichia coli DNA andmultiplying the result in the E. coli culture (1). In 1973,
Stanley Norman Cohen of Stanford University and Herbert
Wayne Boyer of the University of California, San Francisco
created a hybrid plasmid with eukaryotic cell and prokaryotic
cell DNA, using restriction enzymes, which cleave DNA,and DNA ligase, which joins DNA strands together, andconfirmed that this produced RNA in E. coli (2, 3). These
technologies were recombinant DNA technologies thatenabled humanity to cross the “barrier between species”.
However, for some reason, Boyer and Cohen were notawarded the Nobel Prize. Another Cohen did receive theNobel Prize in Physiology or Medicine: Seymour Stanley
Cohen in 1986, for discoveries relating to nerve growth
factor.
Eventually, the basic technology was completed to be able
to produce large volumes of special proteins from the geneproduced by inserting other genes into E. coli plasmids andmultiplying the recombined DNA with the E. coli. The firstsuccessful case of genetic engineering in Japan was in 1977
(4)
. The technology was actively incorporated into agriculture
and animal husbandry; by 1986, tobacco was being produced
that was resistant to disease and pests. By 1994, geneticallymodified tomatoes were being marketed in the United States.
In the pharmaceuticals industry, the main target areas
were polymeric hormones, protein enzymes and cytokines;
the first successful biopharmaceutical product was insulin.
Despite the ongoing postwar demand for insulin, there wereside effects to using porcine or bovine insulin and there was

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchtreatment.
Biopharmaceuticals are polymeric drugs comprising
mainly proteins; these are produced using animal cells andgene recombination. Given the ease of producing proteins
with biotechnology, as mentioned above in the example ofinsulin, the focus turned to antibody preparations as well as
hormones, enzymes, cytokines and other in vivo substances.
There were high hopes for biopharmaceuticals and the late1980s saw growth in the market expanded as epoch-making
pharmaceuticals began to appear.
Between 1980 and 1989, new drug approval was given forsix types of α, β and γ interferons; six types of growth
hormones (somatotropin) were also approved between 1980
and 1990. However, despite being a secret weapon against
the previously-incurable Hepatitis C, the early interferons
had strong side effects and sales slumped as these were not
adopted for clinical use and failed to demonstrate adequate
medicinal efficacy.
Other in vivo hormone and enzyme biopharmaceuticals
were developed; however, many of these were accompanied
by side effects, despite being in vivo substances. Many also
failed to demonstrate the anticipated medicinal efficacy. As aresult, biopharmaceuticals were limited to niche areas, suchas intractable diseases and hereditary enzyme deficiencies.
Substances such as α-galactosidase, α-L-iduronidase andblood coagulation factor were used for patients with
incurable enzyme deficiencies, but were not widely adopted
for general illnesses (see Table 2.7: Biopharmaceuticals
Market Table).

also the issue of the cost of producing semi-synthetic humaninsulin from porcine insulin; the hope was to mass produce
human insulin.
In the early 1970s in the United States, research began on
producing human insulin by mass cultivation after splicing
the human insulin gene into microbial plasmids. In 1978,
Arthur Riggs and Keiichi Itakura of Genentech and the Cityof Hope National Medical Center in the United Statesdeveloped the “proinsulin method” of chemicallysynthesizing the DNA equivalent of the A and B chains of
insulin, splicing these into plasmids to produce proinsulin in
E. coli, and then using a chemical reaction to produce a
double strand. Eli Lilly & Co. adopted this method and in1983 launched Humalin®, an insulin formulation produced
by genetic modification (5).
In 1987, Novo successfully developed its own“mini-proinsulin method” of producing insulin precursor
mini-proinsulin with yeast fungus and converting it into
human insulin. In Japan, approval for human insulin had
been granted in 1985. Developments and improvements havecontinued since then to the time of writing in 2014, withfaster-acting, longer-lasting and sustained-acting
formulations being achieved by partial modification of aminoacids and binding with fatty acids to coordinate the onset andmetabolism of the medicinal efficacy, as well as thedevelopment of insulin analogs by specialized overseas
manufacturers (6).
Insulin was followed by genetically-engineering growth
hormones and interferons; these began to be used in medical

Table 2.7 Biopharmaceuticals Market Table (7)1980-1990

1990-2000

2000-20102010-2014

0
0
0
0

1
2
0
2

7
0
1
2

1
0
0
1

0
1
3
0

4
1
3
0

3
5
2

1
2
0
0

0
4
2
0
2
3
2
1
6

3
7
1
0
1
0
0
0
0

0
8
0
1
1
3
2
0
5

3
5
0
1
1
0
0
0
0

0
0
0
0
0

2
3
2
0
5

1
0
0
1
1

1
0
0
0
0

0

1

14

13

0

0

1

3

12

19

42

30

EnzymesBloodcoagulation
fibrinolytic
systemtPA
Thrombomodulin
Blood coagulation
factorHormones

Insulin
Growth hormones
Follicle stimulating
hormones
Other

Vaccines

Hepatitis
HPVInterferonsαβγ

Erythropoietin
Cytokines

G-CSF
Interleukin 2
FGF

Antibodies
Fusion proteins

Total

Systematized Survey on the History of Drug Discovery with Technical Development

49

Erythropoietin (EPO) and granulocyte-colony stimulating
factor (G-CSF) were large-scale biopharmaceuticals.
Erythropoietin is a glycoprotein hormone with a molecularweight of 30,000; it promotes the differentiation of erythroid
stem cells and the production red blood cells. G-CSF is acytokine with a molecular weight of 19,000; it is a proteinthat promotes the production of granulocytes and boosts thefunction of neutrophils.
In 1977, Takaji Miyake of Kumamoto University Schoolof Medicine announced that he had refined EPO from humanurine. In 1985, US companies Amgen and Genetics Instituteannounced the successful production of EPO by generecombination. Both groups had started researching using
Miyake’s EPO extracted from urine (10mg of refinederythropoietin from 2.5 tons of urine from aplastic anemia
patients).
A patent dispute ensued from 1987 to 1992 between
Amgen and Genetics Institute, which had joined forces with
Miyake; Amgen was ultimately the winner.
In Japan, Kirin signed a contract with Amgen and started
working on domestic clinical development, while Chugai
Pharmaceutical did the same with Genetics Institute. In 1990,
Kirin was granted manufacturing approval for a humanerythropoietin formulation (epoetin-α) made using generecombination technology as a treatment for renal anemia
during dialysis. Chugai gained approval for eopetin-β in
1990 as well, also as an effective treatment for renal anemia
during dialysis.
According to the 1990 predictions for the future of thebioindustry in Survey of Trends in Technology Patent
Applications to the Japan Patent Office, the genomic drug
discovery market would be worth ¥5.4 trillion by 2020, genetherapy would be worth ¥2.7 trillion, genetic diagnosis ¥720
billion and regenerative medicine ¥2.3 trillion. In reality, theestimates took a major downturn, with biopharmaceuticals
slumping from the 1990s to the 2000s.
However, with the advent of the 21st century, it was foundthat antibodies that target specific cells in specific proteins
have a significant medicinal efficacy in the fields of
oncology and immunology (Note 1). A number of companies
started investing into research and development in theseareas, thus breathing new life and significant development
into biopharmaceuticals. At present, the fields of oncology
and immunology are the most active fields forbiopharmaceuticals.
According to materials produced by the National Instituteof Health Sciences Bio Division, 26 types of antibody drugs
were marketed between 2000 and 2014 (7). The main key
technologies in these antibody drugs were humanization
technologies, in which mouse genes are replaced by humangenes, and technologies to produce human immunoglobulin
using cultivated Chinese hamster ovary (CHO) cells. There
have been a number of achievements in these fields;
advances in technology have rapidly made it possible tosafely mass produce these drug products, while the use of50

human antibodies has meant drastic reductions in side effects
and greater ease in clinical trials.
Biopharmaceuticals have also made it possible to target
cancers and autoimmune disorders, which had not beenpossible to properly deal with using low-molecular-weightdrugs. Successive new drug products began to emerge on themarket. The 26 antibodies mentioned above included 14
types of anticancer drugs and 6 types of immunity-relatedbiopharmaceuticals used for rheumatoid arthritis, renaltransplants and the like (see Table 2.7).
Japanese scientists have made significant contributions in
the field of antibodies. The mechanism of how the body
produces such a diverse range of antibodies that bind toinnumerable proteins using a limited number of genes had
long been a mystery in immunology. The question was
finally and brilliantly answered with a theory proposed by
Susumu Tonegawa, who was awarded the Nobel Prize inPhysiology or Medicine in 1987. The theory suggests thatvariable region genes are formed by an H-chain gene, forinstance, randomly selecting and binding to antibody genefragments present in different areas V, D and J; thecombination of these allows a great diversity of antibodies tobe produced.
Other known phenomena include immunoglobulin classswitching, in which the constant-region portion of a sequencechanges when the antibody gene is mature, and somatic
hypermutation, which allows further adaptation of thevariable region; research by Tasuku Honjo made asignificant contribution to understanding these phenomena.
While such technology has made it possible to produce
large quantities of human-type monoclonal antibodies,
production for antibody drugs requires massive cultivation
facilities and significant research and development expenses.
Meanwhile, where biopharmaceuticals have struggled togain traction, biotechnology has played a major role in theform of tools (supporting technologies) for
low-molecular-weight drug discovery. These technologies
have included: microarrays and other forms of chiptechnology; automatic cell separators for separating cells;
polymerase chain reaction (PCR) as a method of replicating
DNA (Note 2); DNA sequencers for automatically determiningbase sequences; and peptide sequencers for automaticallyanalyzing the amino acid sequences of proteins.
These technologies have been put to use in genomic drug
discovery (Note 3) for discovering and validating new targets
for low-molecular-weight drugs. Pathological animal models
are essential for evaluating new drugs and many
contributions to research and development have enabled by
the creation of knockout mice, which have certain genes
inactivated, and transgenic mice, which have genes
transferred into them. However, with the focus on animal
welfare in recent years, research has also gone into methods
that substitute the pathological animal models with in vitro
testing; biotechnology can be expected to be utilized in thisarea as well.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchAdvances have also been made in cell biology, with
Yoshio Okada making a ground-breaking andand screening leading to drug discovery. See Chapter 3.

highly-impacting discovery in 1957 with his paper on cellfusion using Sendai virus. It has since been found that cellfusion is possible with other animals; cell fusion has become
one of the mainstays of biotechnology, with dramatic
progress being made in cellular-level genetics and inresearch on viral carcinogenesis.
Various cell differentiation and regeneration technologies
have emerged, such as gene therapy, cloned animals,
embryonic stem cells (ES cells) and induced pluripotent stem
cells (iPS cells), pioneered by Shinya Yamanaka, who wasawarded the Nobel Prize in Physiology or Medicine in 2012.
While the ultimate use for these technologies will be
regenerative medicine, there are a number of factors involved
and there will be a number of challenges to face, not only interms of medicinal efficacy and treatment, but also in termsof the mass production of cells, such as ensuring a stablesupply of culture fluid free from viruses and othercontaminants, steady production using cultivation andrefining processes, ensuring product quality, having therelevant inspection and validation systems, reducing
timeframes and keeping costs down.
These regenerative-medicine-related technologies are
currently being used as tools to support drug discovery.
Biotechnology is being accumulated in the target discovery
and target validation (see Chapter 3) part of the drug
discovery process and can be expected to make a significant
contribution to new drug discovery in the 21st century. Initial
screening using human cells and tissues has been
problematic, but the use of iPS technology is expected tomake it possible to evaluate drugs in human systems at theearliest stages of drug discovery. The production of knockout
animals and transgenic animals is also being used in drug

References[1] Jackson DA, Symons RH, Berg P.: Biochemical
method for inserting new genetic information into DNA
of Simian 40. Proceedings of National Academy of
Science of USA 69(10): 2904-2909 (1972).
[2] Cohen SN, Chang AC, Boyer HW, Helling RB:
Construction of biologically functional bacterial
plasmids in vitro. Proceedings of National Academy of
Science of USA 70(11): 3240-3244 (1973).
[3] Morrow JF, Cohen SN, Chang AC, Boyer HW,
Goodman HM, Helling RB: Replication andtranscription of eukaryotic DNA in Escherichiacoli:
Proceedings of National Academy of Science of USA.
71(5): 1743-1747 (1974).
[4] K. Nagahari, T. Koshikawa, K. Sakaguchi: Cloning
expression of the leucine gene from Tbermus
thermophiles in Escberibia coli. Gene 10: 137-145(1980).
[5] Taken from the Novo Nordisk company website(2014).
[6] Taken from the Eli Lilly & Co. website (2014).
[7] Public document: Wagakuni de Hatsubai Sareta
Baio-iyakuhin (Biopharmaceuticals released in Japan).
National Institute of Health Sciences, Division of
Biological Chemistry and Biologicals. Revised April
2014.
[8] Product release dates, indications and other details
taken from the drug interview forms from the various
companies.

discovery research as technology has advanced.
2.4.7.
Note 1: Antibody drugs: When an antibody specifically binds to a

Medicines in Japan (Part 3: Current
Pharmaceuticals Industry)

specific protein, that protein ceases to perform its original function.
The use of antibodies on key cancer-cell-activating proteins can be
expected to have an anti-cancer effect by inhibiting the activation of
the cancer cells.
Note 2: Polymerase chain reaction (PCR) is a DNA replicating
technology using DNA polymerase, invented by Kary Banks Mullis,
who was awarded the Nobel Prize in Chemistry in 1993. It has had asignificant impact on molecular biology. It is also known for its use
in criminal investigations; the PCR method is used to amplify DNA
from billions to hundreds of billions for DNA testing.
Note 3: Genomic drug discovery: The incorporation of genome
analysis and genome-related technologies into drug discovery.
Genomic drug discovery includes using these technologies in finding
and validating drug discovery targets, as well as in methodologies

Changes in the Pharmaceuticals Market
According to the Ministry of Health, Labour andWelfare’s Vision for the Pharmaceutical Industry 2013, theJapanese pharmaceuticals market was worth ¥9.3 trillion in
2011, with ethical pharmaceuticals accounting for ¥8.7
trillion and the over-the-counter drug market making up theremaining 7%. In 2000, the market was worth ¥6.7 trillion,
with ethical pharmaceuticals accounting for 88% at ¥5.9
trillion and over-the-counter drugs accounting for 12%.
During the decade in between, there were calls to reduce
medical expenses each year; measures included bring down
drug prices and promoting the use of generic drugs.
Nevertheless, the ethical pharmaceuticals market hascontinued to grow in terms of turnover; total medical
expenditure has continued to increase during this ten-year

Systematized Survey on the History of Drug Discovery with Technical Development

51

Otherperiod, with drug costs remaining at 20-22% (see Figure2.14) (1).

Germany

trillion yen

FranceUnited Kingdom

National healthexpenditure (¥1tn)

Japan
Switzerland
United States

Drug costs / medical
expenditure (%)

Drug costs (¥1tn)

2011 Pharmaceutical Market Share by Country
From MHLW Vision for the Pharmaceutical Industry 2013

Fig. 2.15

Market Share by Country of the 30
Highest-Selling Pharmaceutical Companies

Fig. 2.14 Recent Trends in National HealthExpenditure / Drug Costs (1991-2009).
Chart drawn from MHLW document Vision for the PharmaceuticalIndustry 2013 (p. 4, 2013)

Looking back, ethical pharmaceutical production rosefrom ¥770 billion in 1970 to around ¥3 billion by 1980 (agrowth factor of 3.9 in ten years); by 1990, it had risen to¥4.7 trillion (growth factor of 1.6 in ten years) and by 1995,
it had risen to ¥5.2 trillion (growth factor of 1.1 in five
years).
The global market hit $726 billion in 2007; by 2011, it
had grown to $953 billion, with annual growth in the markets
outside of Japan in Asia, Africa and Central and SouthAmerica. On the world market, Japan has been second only
to the United States since the 1980s; its 2011 market share of$111.6 billion accounted for 11.7% of the global market,
rivalling the $114 billion of Germany, France and Italy
combined.
Between 2007 and 2011, North America (United States
and Canada) occupied 36-40% of the global market; duringthat time, Japan took second place at around 10%. Looking
further back, the Japanese market occupied 15% of the world
market in 1985, rising to 19% by 1990 and 21% by 1995.
Since then, the Japanese market share has started to decline,
returning to 15% by 2000 (2). These figures have earned theJapanese a reputation as the world’s most medicine-loving
nation. After that, the global market started growing indeveloping nations, giving the Japanese market theappearance of a relative decline.
Figure 2.15 shows the market share of the 30
highest-selling pharmaceutical companies by country. While
Takeda Pharmaceutical is the only Japanese company in the
top ten, Japan still ranks third highest among the total 30.

52(2011).
(from MHLW document Vision for the Pharmaceutical Industry 2013, p.
16, 2013)

Opinions are divided as to how to interpret these figures.
Japanese drug discovery companies have continued theirresearch and development focused on pharmaceuticals forthe domestic market; this policy has not kept them abreast of
global changes. It is important to adopt a global strategy forthe future while also maintaining the strategy of drug
discovery for the domestic market.
Recent research has found that due to polymorphisms andsingle nucleotide polymorphisms (SNPs), different
individuals produce proteins with different amino acidsequences, meaning that drugs work in different ways in
different individuals. These genetic differences not only
occur between individuals, but also between races; thedifficulty of discovering drugs that work for all people
irrespective of race is beginning to be understood.
Consideration is being given to the idea of drug discovery
branching in two different directions: drugs that can be usedby all people and drugs that are administered to specificindividuals or races.
Original Drugs and Generic Drugs
There are two types of pharmaceutical products: ethicalpharmaceuticals, which require a medical prescription, andover-the-counter (non-prescription) drugs, which can bepurchased at any drugstore. Ethical pharmaceuticals
comprise original drugs and generic drugs, which aremarketed after the patent period of the original drug has
expired. In Japan, the original drug market grew from 17% to
23% in volume terms and from 5.9% to 8.8% in value terms
between 2007 and 2011 (1).
There are substantial costs involved in the research anddevelopment of generic drugs; it can cost over ¥10 billion in
research and development to produce a single drug,
especially if the clinical trial is large in scale. Taking into
account the research and development of new drugs that have

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchbeen discontinued, this area of research and development iscosting tens of billions of yen. The average research anddevelopment expense in the pharmaceutical industry in 2011
was 12% of sales, higher by far than the 6.44% in thetelecommunications device manufacturing industry, the
6.39% in the electronic circuits and components
manufacturing industry, the 5.9% in the electrical machineryand device manufacturing industry and the 4.78% in theautomobile and accessories manufacturing industry. Thisratio has hardly changed since the 1980s (4).
Meanwhile, patients are also becoming more aware, as theadministration of generic drugs is being encouraged as ameans of reducing costs. An increasing number of leading
companies are also starting to sell generic drugs. There is arenewed acknowledgement of the importance of low-priced
pharmaceutical products with guaranteed safety and efficacy.
Nevertheless, even under such circumstances, companies
need to maintain and increase their turnover for the sake ofbusiness. There is a growing emphasis on new drug researchand development to play a role in driving growth. Releasing
a blockbuster drug on the market requires faultless target
setting that hits close to the true cause of a disease; it also
necessitates increasing the speed of research anddevelopment, which requires a rapid feedback system todetermine overall efficacy and side effects, as well as
efficient research and development facilities. Much can be
expected from companies utilizing their strengths andcreativity.
The Domestic Market by Field of Disease
The proportional shipment volumes for the top four drugclassifications on the Japanese market for 2011 have hardly
changed since the 1990s, with (i) circulatory system drugs(anti-hypertensives, hyperlipidemia medications, heart
medications, etc.) accounting for 16.6%, (ii) central nervous
system drugs (medications for depression, anxiety,schizophrenia, dementia, antipyretic analgesics, etc.)
accounting for 10.8%, (iii) other metabolic drugs (diabetes
medications, liver medications, etc.) accounting for 10.3%
and (iv) gastrointestinal drugs (antiulcer medications,stomach medications, intestine medications, etc.) accounting
for 7.4%.
One major change is that of antibiotics dropping fromsecond place in 1990 to fifth place by 2000 and out of the top
ten by 2011. As the hygiene and nutritional environments
improved and peoples’ general medical knowledge increased,
infectious diseases reduced and the administration of
unnecessary antibiotics and chemotherapeutics also
decreased. The Japanese were also losing faith in antibiotics.
Metabolic drugs held fifth position in 1990 and later rose
into the top four. Anticancer drugs, which were notnumbered among the top ten in 1990, had risen to eighth
place by 2005 and to fifth place by 2011 (see Table 2.8).

Table 2.8 Domestic Market Share of Shipments by DrugClassification
1990
2000
Drug classification(share)Circulatory
13.8 Circulatory
system drugs% system drugs
Antibiotics
11.2 Gastrointestin
al drugs
Centralnervoussystem drugs
Gastrointestin
al drugs
Metabolic
drugs
Skin
medications
Diagnostic
agentsVitamins
Respiratory
drugs
Blood/body
fluid
medications
Other

9.2 Central
nervoussystem drugs
8.9 Metabolicdrugs
7.9 Antibiotics
5.7 Skin
medications
5.6 Blood/body
fluid
medications
4.7 Biologicalpreparations
4.5 Sensory organdrugs
3.1 Hormone
drugs
25.3 Other

2005

2011

16.9 Circulatory% system drugs
8.2 Metabolic
drugs

18.1 Circulatory% system drugs
9.4 Central
nervoussystem drugs
9.3 Metabolic
drugs

16.6
%
10.8

8.0 Gastrointestin
al drugs
4.8 Tumor drugs

7.4

4.6 Biologicalpreparations
4.5 Blood/body
fluid
medications
4.4 Allergy drugs

5.3

5.0 Blood/body
fluid
medications
4.2 Tumor drugs
3.8 Biologicalpreparations
3.7 Sensory organ
drugs

4.0 Skin
medications
3.6 Sensory organ
drugs

4.0

29.9 Other

29.4 Other

25.8

8.1 Central
nervoussystem drugs
8.1 Gastrointestin
al drugs
6.2 Skin
medications
5.9 Antibiotics

10.3

7.3

5.1

4.1

3.5

(from MHLW documents Vision for the Pharmaceutical Industry 2013, p.
14, and Statistics of Production by Pharmaceutical Industry)

This table indicates that lifestyle-related diseases andcancers have become the focal diseases of the 21st century.
Drugs for lifestyle-related diseases, now more than ever at
the focus among pharmaceutical products, have reached astate of near completion from a technology perspective.
However, like the course taken by vitamins and antibiotics
from the 1950s to the 1980s, these drugs, too, can be
expected to follow a similar pattern, passing from an“in-demand new drug stage” to an “ongoing sales stage”,
followed by “eventual reduce in demand”. Consideration will
be needed as to how to maintain sales in future.
Gastrointestinal drug sales also generate high figured andhave long held a top ranking. While oral antiulcer
medications (H2 inhibitors and proton pump inhibitors) areadministered in high numbers, the administration of stomach
and intestine medications alongside other drugs also
contributes to these figures.
Anticancer drugs are a major target for such concomitantdrug administration. This field requires a concept unlike thatof conventional pharmaceuticals; consideration needs to begiven to “individualized medicine” that incorporates the useof biotechnology and diagnostic examination.
Globalization of the Pharmaceuticals Industry
According to the MHLW’s Statistics of Production by
Pharmaceutical Industry, shipments by foreign-capitalenterprises accounted for 36.2% of the total pharmaceuticalproduct shipments on the domestic market in 2011. At 18.6%
in 1991, this figure has more than doubled in ten years (1).
The proportion of overseas sales by Japanese companies
has remained level at around 35-37% of total sales since
2007.
In terms of research and development, according to thelatest documentation from the Ministry of Health, Labour

Systematized Survey on the History of Drug Discovery with Technical Development

53

and W2elfare, Japan approved 89 new active ingredients
between April 2008 and May 2012, 49.4% of which wereresearched, developed and produced by Japanese companies,
while the remainder were imported from overseas (foritemized details on the new drugs by the Japanese companies,
see the Central Social Insurance Medical Council (82nd)Special Committee on Drug Prices, August 22, 2012; expert
committee members Kanji Negi and Yoshiaki Kamoya).
From the 1970s onwards there was a shift away from thelong-lasting postwar era that gave precedence to imported
drugs and an increase in domestically-produced products,
although these were mainly improved formulations. Whilesome innovative new drugs did emerge as well, overseas
imports have again been on the rise. In an age of increasingly
individualized medicines, there is a need to develop drugs fordomestic production. Attention needs to be given to finding
the balance between globalization (world-perspective
strategies) and “Galapagosization” (domestic-focusedstrategies).

54

References[1] Ministry of Health, Labour and Welfare document:
Vision for the Pharmaceutical Industry 2013, Statisticsof Production by Pharmaceutical Industry (accessed
October 1, 2014).
[2] Ministry of Health, Labour and Welfare document:
Vision for the Pharmaceutical Industry 2013,
Documents p.2: Scale of the Pharmaceutical Industry(Global), Transitions in Sales Figures (accessed October
1, 2014).
[3] Japan Science and Technology Agency Center for
Research and Development Strategy: Overview ofTarget Fields as Seen Through the Data; Itemized
Details on New Drugs by Japanese Companies for 2012
(accessed August 10, 2014).
[4] Ministry of Economy, Trade and Industry, Industrial
Science and Technology Policy and Environment
Bureau, Technology and Research Office: Trends in
Research and Development Related to JapaneseIndustrial Technology – Key Indicators and Survey Data,
13th edition (accessed August 10, 2013).

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

3

Technological Advancement of Pharmaceutical
Drug Discovery (Drug Discovery as a Systems
Science)This paper thus far has discussed the development ofpharmaceutical products in chronological sequence; thischapter now focuses on developments in drug discovery
processes from a technology point of view.

3.1 Drug Point of Action
The body works to maintain homeostasis; however, wheninternal or external abnormal information (stimuli) is
introduced, it confuses the transmission of information(stimulus transduction), thereby disturbing homeostasis. If
this continues, it can cause abnormal conditions in tissues,organs or throughout the body. The role of drugs is to either
eliminate the source of the abnormal information causing thecondition (e.g. eliminating pathogens) or to bring theabnormal information transmission (signal transduction)back to normal (e.g. eliminating inflammatory substancesfrom a site of inflammation).
Drugs demonstrate their efficacy by inhibiting or
promoting the transduction of stimuli within or between cells.
For example, enzyme inhibitors demonstrate their medicinal
efficacy by inhibiting certain enzymes that are working
excessively and thereby prevent the any subsequentmechanisms. Drugs that are receptor antagonists inhibit thetransduction of large amounts of stimuli by antagonizing thereceptors, thereby returning conditions to normal. Drugs thatare receptor agonists invoke the transduction of strong
stimuli by stimulating the impaired receptor function,
thereby returning conditions to normal. See Figure 3.1.
At molecular level, the point of action of drugs is often
protein. According to the literature examining the point ofaction of drugs, as at 2000, (i) receptors accounted for 45%,(ii) enzymes accounted for 28%, (iii) membrane transport
protein accounted for 5% and (iv) nuclear receptors 2%.
Thus, almost 80% of drug discovery targets are enzymes or
receptors (1).
The modern drug discovery process is based on processes
used for screening chemotherapeutic drugs. Since chemicaltreatment targeted pathogenic microorganisms coming fromoutside of the human body, advances in drug discovery wererelatively straightforward.
In the 1950s, James Black discovered histamine H2
receptor antagonists. These were administered to patients
suffering from stomach ulcers and duodenal ulcers, withbreakthrough effects. Thus, the modern drug discovery
research and development process reached a basic level ofcompletion. This process is summarized in Figure 3.2.

Typical points of action include (i) receptors and(ii) enzymes.
E.g.
(1) Receptor antagonist effectDrug

Angiotensin 2 (shown as A in the left figure) binds to the AT1 receptor;
stimuli are transmitted and the arterioles contract. This causes
hypertension.
The antagonist blocks the binding of A, resulting in a hypotensive effect.
Smooth muscle cell
Arteriole
contraction

Hypertension

Stimulustransduction

AT1 receptor(2) Enzyme
inhibiting effectDrug

Angiotensin 1(shown as a in the left figure) forms angiotensin 2 (= A)through the action of angiotensin-converting enzyme (ACE). Inhibiting
ACE prevents the production of A, thereby inhibiting arteriole
contraction, resulting in a hypotensive effect.

As enzymes are also involved in stimulus transduction,
anti-hypertensives using enzyme inhibition are also considered.

Fig. 3.1 Point of Action of Drugs. (see Section 4.2.4. Renin-Angiotensin System for details on anti-hypertensives)

Systematized Survey on the History of Drug Discovery with Technical Development

55

Screening
Hit → leadHit discovery

Target discovery
Target validation

Lead
ClinicalCandidate compound
optimization Preclinical evaluation development

LeadcompoundTargetsetting

Candidatecompound

Improved new
drugs~1980s Discovery of modern new drugs
Searching for blockbuster drugs

1990s The age of drug discovery technology as asystems science
2000s

Towards an age of utilizing genomic drug discovery and individualized medicine
From genetic diagnosis to drug
administration

Target expansion

Until the 1980s, there were more “improved drugs” using known lead compounds than innovative drugs using lead compounds with new
structural formulas. By the 1990s, science and technology had built up to the point that drug discovery could be referred to as a systems science.
It became possible to narrow down theoretical candidate compounds from greater numbers of compounds. The 2000s saw the dawning of theage of genomic drug discovery, with targets emerging that differed from existing ideas. The ties between clinic and base field grew stronger;
patients were selected with coordinated consideration between diagnosis and drugs; drugs began to be administered with more reliable medicinal
efficacy. Since it takes 15-20 years for pharmaceutical products to reach the market, the products being marketed in the 2010s are the results ofdrug discovery research and development in the 1990s. The results of genomic drug discovery are yet to emerge.
In pharmaceutical product research and development, clinical trials are often referred to as “development”, while the preceding processes areoften referred to as “research”.

Fig. 3.2

Drug Discovery Process Development.

3.2 Changes in Drug Discovery Processes

and the emergence of the term “target discovery” (Note 1), in
which gene analysis is used to find new targets for diseases.

This explanation of the drug discovery process follows thecourse shown in Figure 3.2.
(1) Target Discovery and Setting
Determining drug targets requires determining the target
disease and determining the proteins on which the drug willact (this is best discussed in terms of protein, since mosttargets are currently proteins). Targets are determined inconsideration for disease/patient trends, their necessity inclinical practice and the clarification and differentiation ofpoints of improvement to existing drugs, as well as the points
of difference with existing drugs for factors such as sales andprofitability from a business perspective.
Receptors or enzymes were chosen as targets in the
postwar era; as mentioned previously, these were the main
drug targets for a long time. Although there is not necessarily
one single target for a certain disease, selecting pre-existing
drugs meant the target was the same. There are not any
substantially significant differences between these drugs interms of medicinal efficacy; they are categorized by theirside effects and methods of administration. Drugs discovered
using this type of target selection are referred to as“improved drugs”.
The late 1990s saw the advent of genomic drug discovery

56(2) Establishing Evaluation/Selection Systems(Screening Systems)
The so-called screening stage is termed “drug discovery”
and encompasses everything from discovering hit
compounds to optimizing lead compounds. This process firstrequires the creation of a screening system. The first stage
examines whether or not a compound is possible to be used
as a drug. This system must be very simple and repeatable inorder to process large numbers of compounds. This is where
different companies put their own ingenuity into action.
• in vitro testing systems (testing systems carried out in test
tubes or Petri dishes; enzymes or receptors are used in
crude or refined form; tissues or cells also used)• in vivo testing systems (medicinal efficacy evaluation
system using entire animals; pathogenic animal models,etc.)• in silico systems (in genomic drug discovery, a method ofscreening for hit compounds and lead compounds bycomputer based on past information)(3) Lead Compound Setting
Lead compound setting refers to screening large numbersof compounds and then determining the basic skeleton of thecompounds to be evaluated. Any compounds exceeding theinitial criteria for efficacy, drug metabolism, safety, etc. are

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchselected as lead compounds.
• Where the lead compound is a known drug
While compound setting is easier with a basic skeleton
already in place, it is more difficult to demonstrate any new
drug characteristics if the structure of the compound does not
greatly differ from existing drugs. Many of the drugs known
as improved drugs started with a known lead compound andresulted from the synthesizing and evaluating of peripheral
compounds. Although this method is known as Japan’s forte,
it is very common in the West as well, with numerous
improved drugs emerging on the heels of every innovative
new drug (Note 2).
• Where the lead compound is set by random screening
In the absence of a basic skeleton for reference, leadcompounds can be selected by screening compounds at
random. A group of compounds used randomly is called a“compound library”; each company has access to their own
collection of compounds. More important than the number ofcompounds in the collection is the variety of basic skeletons;
the greater the variety, the higher the chance of theevaluation system making a hit. A company’s compound
library represents the compound characteristics available tothat company and reveals the originality of the company.
Synthetic compounds are not the only targets forscreening. Fungus or mold culture filtrates and plant extracts
are also used in order to extend the breadth of the basic
skeletons available.
While many antibiotics are derived from fungus or mold,the world-class breakthrough drug Pravastatin from Japanand the globally innovative immunosuppressant Tacrolimus
by Fujisawa Pharmaceutical were discovered from fungus
culture filtrates.
It is rare to discover a perfect lead compound with only ashort amount of screening, but it should reveal several
compounds with certain levels of pharmacological activity.
These are called “hit compounds”. Where multiple hit
compounds share a common chemical structure (basic
skeleton), it means they have a “pharmacophore” (2), or “theensemble of steric and electronic features that is necessary toensure the optimal supramolecular interactions with a
specific biological target structure and to trigger (or to block)its biological response” (Note 3).
Based on this information, medicinal chemists presume astructure-activity correlation and start to narrow down leadcompounds by altering side chain molecules, thereby
enhancing the medicinal efficacy and reducing the side effects.
(4) Optimization
Having obtained a lead compound, further chemical
modification is carried out in detail on the compound to
produce a more active development candidate compoundwith fewer side effects; this is called “optimization”. This iswhere medicinal chemists need to have ideas andtechnological prowess.

In the optimization process, medicinal efficacy isevaluated using multiple evaluation systems rather than on asingle screening system alone; this includes testing on
several pathological animal models. These evaluations not
only serve to validate medicinal efficacy, but also to checkfor toxicity using simple toxicity tests and affirm that thecompound has good pharmacokinetic properties. Thus, adevelopment candidate compound is selected. This is a major
process requiring coordination between drug evaluation
divisions, compound synthesis divisions, safety evaluation
divisions and pharmacokinetics (Note 4) evaluation divisions.
The respective criteria for each division are important; if thecriteria are too strict, it will be very difficult to produce a
candidate compound, but if the criteria are too lax, thecandidate compound will lack originality. Japanese drug
discovery companies have had systems in place to connect
these divisions since the 1980s (see Section 2.4.1).
(5) Preclinical Testing (Nonclinical Testing)Once a development candidate compound is selected, thenecessary testing for clinical adoption is then carried out inaccordance with good laboratory practice (GLP). This testing
is known as preclinical testing (or sometimes, nonclinicaltesting). This includes validating the medicinal efficacy,
safety testing, pharmacokinetic testing and setting candidate
compound criteria, as well as chronic safety testing,medicinal efficacy testing on animal models and testinglarge-scale synthesis methods for setting criteria.
GLP is a set of standards applicable to testing laboratories
in order to ensure the reliability of nonclinical testing in
relation to safety. These were first established in the UnitedStates in 1979. In 1981, the OECD formulated GLP
standards and indicated that member countries should
introduce GLP based on these standards, prompting theestablishment of various kinds of GLP in many countries.
Japan enacted GLP standards for medical and pharmaceuticalproducts in 1983. These underwent subsequent changes,
including being codified into a Ministry of Health, Labourand Welfare ordinance and being adopted forpharmacological safety testing. GLP was written into aministerial ordinance in 1997 (see Section 2.4.1 above).
There are six GLP programs in Japan: medical andpharmaceutical products / medical equipment; industrial
safety and health (Industrial Safety and Health Law); newchemical substances (Chemical Substances Control Law);
agricultural chemicals; feed additives; and veterinary
medical and pharmaceutical products / veterinary medical
equipment. These are governed by four regulatory authorities(3, 4, 5, 6).
Good manufacturing practice (GMP) is a set of standards
that determine matters relating to the appropriate
manufacturing control and quality control methods to beobserved when manufacturing investigational new drugs, aswell as the necessary structures and facilities. GMP wasestablished in the United States in 1963 following instancesof harmful side effects from drugs. In 1969, the World
Health Organization (WHO) endorsed requirements for goodpractices in the manufacture and quality control of drugs. In
Japan, the Ministry of Health and Welfare notified theadministrative divisions of Japan of these requirements ascriteria for the manufacture and quality control of drugs in
1974. Meanwhile, the Japan Pharmaceutical Manufacturers
Association (JPMA) had already established its own
independent criteria (JGMP) in 1973, having investigated theestablishment of GMP of its own volition. GMP was

Systematized Survey on the History of Drug Discovery with Technical Development

57

promulgated as an ordinance of the Ministry of Health andWelfare in 1980 (7, 8). A summary of these drug discovery
processes is shown in Tables 3.1 and 3.2.
Table 3.1

Drug Discovery Process (Exploratory Research)

Exploratory Research Stage
Seeking/Creating Candidate Substances
Drug Discovery
Target Discovery
Drug Discovery initial
subsequent exploratory
basic research
exploratory researchresearch• selection of drug • discovering hit
targets
compounds
Candidate compound
optimization• target validation• discovering leadcompounds• concept validation Securing evaluation
Drug design(patenting /samples• medicinal efficacy
competition /• synthesized / natural • pharmacokinetics
market / medical(preliminary testing)/ biosynthesizedenvironment /products• safety (preliminary
medical needs,• combi-chem sample
testing)etc.)
Screening test
Testing with composite• establishing• general screening
evaluation systems
activity evaluation • in silico screening(in vitro/in vivo testing)systems• HTS• target validation(verification)
MBC internal document, revised 2006: Mitsubishi Chemical BCL Co., Ltd.

Table 3.2

Drug Discovery Process (Preclinical Testing Stage)

Preclinical Testing Stage
Validation/Suitability Evaluation of Candidate Compounds for Clinical
Trials
GLP/GMP Conformance
validate structure / research substance production
Synthesis/Bio
methods / secure large volume of samples
formulation design / research formulation production
Formulation
methods / produce formulation samples
research physical properties and analysis methods /Quality
set criteria
Assurance
safety testing (substance/formulation)
Medicinal
high-order efficacy evaluation / analyze mechanism
Efficacyof action / safety evaluation testing
investigate measurement methods / investigate
Pharmacokinetics
pharmacokinetics and metabolites
general toxicity (single/repeated dose) / TK testing /genotoxicity (mutagenicity)
Safetyreproductive and developmental toxicity (Seg I, II:after normal clinical stage) / special toxicity
Testing is carried out at GLP-compliant facilities, in accordance with
Ministry of Health and Welfare Ordinance No. 21

MBC internal document,
revised 2006

(6) Clinical Trials
Clinical trials (clinical testing) are clinical tests carried out
from Phase I to Phase III in accordance with GCP.
• Phase I involves safety testing using on a small number ofhealthy individuals (volunteers) who have provided
consent.
• Phase II involves confirming efficacy, safe dosage levels,
methods of administration and other factors on a small
number of patients who have provided consent.
• Phase III involves confirming new drug efficacy andsafety by carrying out double-blind trials and othercomparative studies against existing drugs on a large
number of patients who have provided consent. Quite anumber of clinical trials have groups with several
thousand participants in them.
Good clinical practice (GCP) refers to standards relating
to the implementation of clinical trials for medical andpharmaceutical products. It is an international set ofstandards enacted to ensure that clinical trials are carried out
appropriately; in Japan, these have been summarized in
Ministry of Health, Labour and Welfare ordinances. Theinternational standards aim to ensure that the human rights
and safety of volunteers participating in clinical trials aremaintained, that medical and pharmaceutical products are58

developed scientifically and that drug information isrecorded accurately during development. Following thepromulgation of the Ordinance on Standards for ClinicalStudies of Pharmaceuticals in 1985, this was established as
an administrative directive in 1988 by the director of thePharmaceutical Affairs Bureau and was put into practice in1990. The so-called New GCP Ordinance on Standards forClinical Studies of Pharmaceuticals, was enacted in April
1997 and implemented the following year in 1998 (9).
Once medical efficacy, utility and safety have been
confirmed, drug discovery companies then apply to the
Ministry of Health, Labour and Welfare for production
approval. When an application is received, the Ministry
reviews the overall structure and refers the application to thePharmaceutical Affairs and Food Sanitation Council (anadvisory body for the Ministry of Health, Labour andWelfare) for deliberation based on the review outcome.
Approved pharmaceuticals are granted production and sales
approval by the Minister of Health, Labour and Welfare. A
drug price is then set and the product is put on the market.
Other basic and applied technologies relating to drug
discovery include systems for regulating drug absorption,
distribution, metabolism and excretion, for ensuring prompt
delivery to and prolonged retention at the target location andfor prompt excretion once no longer needed. These make up
the drug delivery system (DDS), also called a drug transportsystem. While some drugs feature cleverly-designed DDSs
from the outset, in many cases approval is given to add thesesystems later to improve any drawbacks identified during
clinical trials, such as appending dosage types. A summaryof these technologies is provided elsewhere.
The basic drug discovery process discussed thus far has
improved and progressed since the 1960s as advances inmedical science, molecular biology, biochemistry andpharmacology have made it possible to analyze the causes of
diseases at molecular level. Rapid improvements in genetic
engineering and molecular biology since the 1970s have also
made it possible to analyze diseases at genetic level, withincreasing genetic information becoming available. The drug
discovery process has become more complex as scientificadvances have been incorporated and now involves quite adiverse range of technologies. Table 3.3 summarizes the drug
discovery process as it relates to clinical trials.
Table 3.3

Drug Discovery Process (Clinical Trials)

Clinical Trial Stage
Exploratory Clinical Efficacy Examination to Confirmatory Clinical
Efficacy Examination
Phase I
Phase IIa
Phase IIb
Phase III
tolerability /efficacy / safety examination of utility trial /pharmacokinetics trial on patients adaptability /double-blind
trial on healthy(pilot trial)
symptom dose comparative trial
individuals
dependence /in an expanded
optimum
clinical trial
application
method anddosage, etc.
(clinical trial: GCP conformance)clinical trial implementation protocol / clinical trial design / biostatistics /institutional review board / clinical trial association structure / initialclinical trial notification and clinical trial consultations / agreement withclinical trial medical institution / informed consent / clinical trialing
monitoring / data management / data analysis / auditing and ensuring
reliability / writing overall clinical trial reports / application
pre-consultation(nonclinical trial)
chronic toxicity testing (rats, dogs, etc.) / reproductive toxicity testing /carcinogenicity testing

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

MBC internal document, revised 2006

In the event that a certain drug is effective, analogs are

It is now possible to compare diseased tissue with normal

synthesized based on its chemical structure and evaluated.

tissue and extract any significantly differing proteins or

The dosage may be lessened by increasing the medicinal

nucleic acids to use as target candidates (12). For example, by

efficacy, thereby comparatively reducing the side effects.

comparing the expression of a healthy individual with that ofThis has been the trend for creating improved drugs in thea patient and analyzing the difference in terms of mRNA andpast. However, with dramatic increases in information about

cDNA, it is now possible to identify the protein that has

genes and proteins thought to be potential drug discovery

changed specifically due to the disease and use that protein

targets for certain diseases, it is becoming increasingly

as a target candidate.

important to validate whether or not a given target actually

Since proteins are considered to function according to athree-dimensional structure, even if an unknown protein isdoes relate to a given disease.
With it now possible to analyze the causes of diseases at

identified, it is possible to examine its three-dimensional

gene level, it has also been found that homeostasis within an

structure and calculate the properties of the new proteinorganism, or aggregate of multi-phase systems, is regulated

based on information from other proteins. It is also possible

through multiple channels and that the target for a single

to predict which molecules and surrounding structuresdisease is not necessarily a single protein or nucleic acid.

(active center) are likely to be involved in its activity.

Drug discovery companies have each had to devise ways

Although vast amounts of information are now thus required,to address issues, such as which targets to select, how theiradvances in information technology have made computers

drugs differ characteristically from other drugs, how to selectcommonplace. The technologies involved in this information

lead compounds more quickly and at which point to makeprocessing are known collectively as bioinformatics.

improvements to safety evaluations and pharmacokinetics

While it is necessary to validate whether a deduced
protein actually relates to a particular disease, pathologicaland with which kinds of trials.
In the 1990s, biotechnology began to progress rapidly.

animal models can be used to determine the importance of

Following the decoding of almost the entire human basethat protein based on pathological changes that occur when

DNA sequence in the international Human Genome Project

the gene responsible for the target protein is prevented fromin 2001 (10, 11), genomic drug discovery research accelerated,

expressing (using knockout mice, etc.). Although it iswith hopes of making effective use of this genomic

difficult to substantiate every candidate protein, if a certain

information to develop new drugs (Note 5). Disease analyses

conjecture could be made during in vitro testing, then thosebegan to be undertaken at gene level based on the newproteins have been put forward for use as candidate proteins.

research sequence of “DNA→ RNA → enzymes / receptors→ drugs (proteins)”. This was the beginning of(2) Evaluation Systems and (3) Lead Compound Setting

pharmacogenomics (drug discovery using gene technology).

In this process, the target protein is used to create

New methods were developed in basic research year byevaluation systems. The efficacy and accuracy of theseyear and were added to the basic process, making the drug

systems are crucial. A method has emerged known as highdiscovery process more complex and more heavily equipped,

throughput screening (HTS), making it possible to process

which also meant greater research expenses. The cost oflarger volumes of samples in shorter lengths of time. Thispharmaceutical research and development continues to risemethod was first put to use in the 1990s by American drug

as clinical trials grow larger in scale and more complex.

manufacturers. The Society for Biomolecular Screening wasestablished in 1994 as a dedicated HTS organization,

Some examples are given for each process below.

followed by the Association for Laboratory Automation in(1) Target Setting

1996. In Japan, the Drug Discovery Research Automation

More than half of current pharmaceutical product targets

Association was formed in 1995 and drug discovery

are receptor or enzyme inhibitors (antagonists) or activators.

companies began to gather together to work on initiatives. To

Developments in biotechnology, molecular biology andbegin with, these focused on technology imports, such as an

genetic analysis technology have resulted in the deduction

introduction to the American approach by Nippon Roche.

and discovery of successive new potential target genes andDifferent companies also worked on their own

proteins, which has meant an excessive increase in new

HTS-integrated evaluation systems using genome technology

target candidates. Verification testing is being carried out toto determine the efficacy of samples comprising not only

determine whether or not these new targets actually relate to

enzymes or proteins, but also cells or specific proteins withincertain diseases; this process is called target validation.

cells.
HTS involves in vitro screening processed by assay robot.
While this has significantly improved screening efficiency, it

Systematized Survey on the History of Drug Discovery with Technical Development59

has also meant the compounds to be evaluated arerate-limited, thus requiring a higher volume of compound
samples. Companies have worked hard to build up their own
compound libraries, using not only synthetic compounds, butalso bacterial culture filtrates.
Combinatorial chemistry, which emerged in the 1990s in
relation to synthetic compounds, has made it possible to meetthe demand for increased numbers of compounds.
Synthesizing individual compounds one at a time was a
time-consuming process. For solid-phase synthesis, thesubstrate for the reaction is bonded to a particular solid-phasesimple substance, such as polystyrene, and the reaction iseffected by the addition of the reaction reagent dissolved in asolvent. The target final product is obtained from on top of
the solid phase during cleanup once the reaction is complete.
This allows compounds to be obtained in a shorter length oftime and with less complicated post-processing than theconventional liquid-phase synthesis. Based on this principle,
the parallel synthesis method and thesubsequently-developed split-mix synthesis method havemade it possible to synthesize larger volumes of compounds
in shorter lengths of time (13).
While there were initially high hopes that combinatorial
chemistry would revolutionize the field of drug discovery, it
had certain drawbacks, such as poor efficiency in the time
taken to establish a synthetic pathway and the inability toensure diversity due to limited numbers of reactions able tobe used. Adulteration from byproducts also interfered withthe evaluation systems, so this has gradually been put to use
at the optimization stage later in the drug discovery screening
process.
Another method is also being used, known as virtual
screening, in which past data is input into a computer andDevelopments in computer technology and the use ofsynchrotron radiation have resulted in astounding advancesin the speed and scope of X-ray structural analysis. SPring-8
is a large-scale synchrotron radiation facility in the
Nishi-Harima region bordering Hyogo and Okayama
Prefectures. It is one of only three third-generationsynchrotron radiation facilities in the world and is able toproduce the highest-level synchrotron radiation in the world.
With these new technologies revealing the active center oftarget molecules, medicinal chemists have begun
incorporating them into optimization, combining
computer-predicted structures with prior experience andinsight (the intuition that comes with experience). The
technology for designing drugs from target protein structures
is known as structure-based drug design (SBDD) (Note 6).
In 1992, the FDA issued guidelines encouraging racemic
switching (14). These guidelines indicated that pharmaceuticals
with enantiomeric structures should not contain a mixture ofenantiomers, but only one enantiomer with medicinal efficacy,in order to prove that the unnecessary enantiomers areharmless when marketed in mixtures.
This determination was made on the basis of a disparity inpharmacokinetic properties of drugs in the past, with somecontaining isomers with strong medicinal effects and somewith strong side effects. The idea was to select drugs withprecedence given to both efficacy and safety. (The Japaneseblockbuster drugs Cravit and Argatroban have been
confirmed by chiral resolution to have only one direction ofactivity (15). Mentioned later: Section 4.4.2.) Following theissuance of these guidelines, research has been conducted on
methods to selectively synthesize only one enantiomer. The
BINAP transition-metal-catalyst reaction, invented by 2001
Nobel Prize in Chemistry recipient Ryoji Noyori, makes it
possible to selectively react an enantiomer (optical isomer)

software is used to predict the structure of the compound.

using the BINAP chiral structure. This has become a useful
method for the purpose of racemic switching (16). Yoshiji(4) Candidate Compound Structural Optimization

Takemoto et al. of Kyoto University have also createdartificial enzymes using the enzyme reaction principle,

New ideas and new technologies are also being
incorporated into this process to further optimize thecompounds thus narrowed down. It is now possible toexamine the three-dimensional structure of the active centerof target proteins using X-ray analysis during refining andcrystallization. Where this once required a certain amount ofprotein crystals, genetic engineering techniques have made it
possible for E. coli or similar to express large quantities ofproteins that normally only exist in miniscule amounts invivo. The greatest obstacle in X-ray structural analysis has
been the process of discovering the conditions forcrystallization. With crystals able to be produced, conditions
are now all set for the ensuing analysis to be carried out
accurately.

making it possible to efficiently synthesize large volumes ofenantiomers (13:68-75).
(5) Preclinical Testing Genomic Drug Discovery
In the 1970s and 1980s, the selection of candidate
compounds at the exploratory stage generally involved
simple safety testing and pharmacokinetic testing as theevaluation criteria. However, once GLP-compliant safety
testing started being incorporated into preclinical testing on
candidate compounds for clinical use, many candidate
compounds were dropped due to safety issues or inadequate
pharmacokinetics. A number of other candidate compounds
have been withdrawn from development as a result of side
effects or pharmacokinetic issues during clinical trials(clinical testing).

60

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchIf a candidate compound is dropped in the latter stage ofclinical trials, as much as two years of chronic safety testingof different types of enzymes; the enzymes all have different
properties and differ significantly in terms of their substrate(required for new drug applications (NAD)) becomes
unnecessary, meaning that the significant costs outlaid in(drug) reactivity. Drug metabolizing enzymes can bepolymorphisms or single nucleotide polymorphisms (SNPs),

producing large volumes of samples and prolonged
high-volume animal testing have been wasted. One reason

depending on the individual; phenotypes also occur, wherean atypical enzyme or abnormal enzyme is expressed withfor reason this is that the evaluation of candidate compounds
at the exploratory stage has historically revolved around

reduced or deficient enzyme activity. Accordingly, drug
metabolism differs between individuals; this is also one of

medicinal efficacy, with not enough evaluation going into
safety and pharmacokinetics; this has become a matter forthe main causes of difference in drug efficacy between
individuals. It is also necessary to get a proper understanding

reconsideration.
Consequently, with the advent of the 21st century, moreof the correlation between drugs and drug metabolizing
enzymes at the animal testing stage; the hope is to develop

straightforward in vitro safety testing without using animals
or using small numbers of animals has been carried out so as

drugs for which individual differences in drug metabolizing
enzymes can be disregarded. It is also becoming preferable

to avoid endlessly repeating high-volume animal testing.
Research to introduce safety evaluations at the early phase of

to determine dosage based on the state of an individual’s
drug metabolizing enzymes. The idea of personalized

drug discovery by examining biomarkers has begun and is
now being implemented. Some safety issues also result frommedicine has come to the fore (also known as tailor-mademedicine, order-made medicine or optimized medicine);

the basic skeleton of the compound; it is now morecommonplace to use research methods that make it possible

although this is still a long way off, the application ofpharmacogenomics has begun to place medicine on the roadto select and develop a number of different lead compoundswith different basic skeletons at the same time.

to the future (20).
With a candidate compound determined, the drugWith the incorporation of high throughput toxicology into
safety testing in order to evaluate multiple samples within ametabolism is examined using animal models inpharmacokinetic testing. If an issue is identified during thisshort space of time, good use is also being made by utilizing
cells of human origin, safety testing on pathological animal

process, it presents a serious setback to development, just as
for safety testing. More than a few pharmaceutical candidate

models and the use of databases for checking the correlation
between compounds and toxicity. There are expectations thatcompounds have been withdrawn from clinical developed
due to pharmacokinetic defects. According to a 1997 report

iPS cells can be used as a drug discovery tool in the area ofin vitro drug discovery screening using human cells and inby the Drug Research Center, of 198 pharmaceuticalcandidate compounds withdrawn from development during

clarifying mechanisms of action.
Toxicogenomics is a new field of science that involves

clinical trials in the United Kingdom, 39% were due topharmacokinetic unsuitability, 30% were due to lack ofidentifying gene expression patterns and using these toclarify mechanisms of toxicity expression. The aim is to

medicinal efficacy and 21% were due to issues with safety(18:87).
The importance is now becoming recognized of not only
carrying out this testing in the latter part of the drug
discovery stage, but also carrying out pharmacokinetic
testing together with drug efficacy testing in order toascertain the pharmacokinetic properties. Policies are
beginning to be devised to incorporate in vitro evaluation
systems from the early stages of drug discovery.

validate gene expression patterns and predict the likelihoodof toxicity expression with increasing accuracy by gathering
vast amounts of known toxicity data and combining this withgenomics and bioinformatics technology.
The aim of toxicoproteomics is to predict toxicity
expression in cells, tissues and organs by detecting functional
proteins secondary to gene expression; this field is being
explored for the purpose of predicting toxicity (17, 18).
Drugs administered orally to humans and animals areoften absorbed from the digestive tract and transported to theliver via the portal vein and then oxidized (hydration, but anoxygenation reaction) and metabolized by drug metabolizing
enzymes. The drug metabolizing enzymes are a group ofoxygenases present in microsomes in liver cells and small
intestine cells; they form a “super family” known as
cytochrome P450. These inherently increase the hydrophilic
properties of drugs, poisons and other xenobiotics, making
them easier to excrete from the body (19).
Drug metabolizing enzymes in humans encompass dozens(6) The Adoption of Genomic Drug Discovery into
Clinical Trials
Despite the increasing research and development costs ofdrug discovery companies, the number of new drugs being
released on the market has actually reduced since themid-1990s in the United States. One such example is therecalled product Vioxx. Researched and developed by Merck,
Vioxx emerged as a selective cyclo-oxygenase II (COX-2)
inhibitor with no digestive tract side effects. It was marketedin the United States in 1999, followed by 80 countries
worldwide, as an anti-inflammatory and anti-rheumatic; itgrew into something of a cash cow for Merck, with sales

Systematized Survey on the History of Drug Discovery with Technical Development

61

reaching around $2.5 billion in 2003. Merck conducted aclinical trial aimed at expanding the application of Vioxx foruse as a secondary prevention for duodenal cancer; however,patients who took the drug for 18 months or more were
found to be with increased risk of myocardial infarction andother heart disease events. Accordingly, the company
announced a voluntary recall on the drug at the end of
September that year. This was a major blow for Merck, as it
not only suffered the loss of all future profits from the drug,
but was also faced with the issue of patient compensation(see Section 2.4.4 Anti-Inflammatories).
A number of drugs other than COX-2 inhibitors were also
subjected to voluntary recalls. The growing public awarenessof side effects meant a greater demand on companies to takeextra care in development. This meant tests to ensure agreater level of safety in clinical trials and at the drug
discovery stage. Clinical trials became longer, leading toincreased research and development costs.
Table 3.4 shows the major pharmaceutical products worth
more than ¥10 billion that had been withdrawn from theAmerican market in the 2000s.
Table 3.4 Pharmaceutical Products Withdrawn from theAmerican Market due to Serious Side Effects
Drug
Manufacturer Generic name
name
RezulinSankyoTroglitazone
Propulsid

Janssen

RaplonOrganon

Baycol

Bayel

Vioxx

Merck

BextraPhizerIndications
type II diabetes
gastrointestinal
diseaseanesthetic

Side effects

liver damage
ventricular
Cisapridetachycardia
Rapacuronium
bronchial spasm
seriousCerivastatin
hyperlipidemia
myopathy
cardiovascular
Rofecoxib anti-inflammatory
damageStevens-Johnson
Valdecoxib
analgesic
syndromeYearYear
approved withdrawn
1997
2000
1993

2000

1999

2001

1997

2001

1999

2004

2001

2005

Source: Excerpt from Shiew-Mei Huang et al.: Toxicology Mechanisms andmethods 16, 89-99 (2006).

Japan started implementing policies to keep drug prices
down as a means of curbing the ever-increasing cost of
medical treatment. However, stricter auditing to ensure new
drugs were safer and more effective meant greater researchand development costs. Drug companies now had to think ofways to carry out their research and development more
efficiently.
There were hopes that the epoch-making arrival in the
2000s of genomic drug discovery and other new drug
discovery technologies would usher in a host of superior
pharmaceutical products with globally-innovative
mechanisms of action, but in fact, contrary to expectation, no
new drugs were developed, other than biopharmaceuticalantibodies. The FDA has indicated that despite a number of
new discoveries in new basic research in recent years, there
are fears that rather than leading to any more usefulpharmaceutical products, these will only lead to longer
development times and more failed developments due toinadequate efficacy and safety evaluation methods.
The Critical Path Initiative promoted by the FDA in 2004
encouraged the creation of better treatments using more
efficient research and development methods with efficacy
and side effects worked out in advance, rather than theconventional development method of trial and error. While in62

the past biomarkers had long been used empirically, many ofthem had no theoretical backing for predictability. Selecting
better biomarkers in future will make it possible to determine
medicinal efficacy and predict side effects more accurately
during the drug discovery process; there are also hopes that
this could be put to use for diagnostic drugs in clinical trials.
Selecting more appropriate biomarkers should reduce thepharmaceutical product dropout rate (21, 22).
The biomarkers indicated by the FDA are biochemical or
biological reactions produced by the body; these include
DNA, m-RNA, proteins, receptors and carbohydrate chains,
as well as blood pressure and positron emission tomography(PET) in a broader sense (23).
Selecting appropriate biomarkers will ultimately lead topersonalized medicine, in which medicinal efficacy and side
effects for an individual can be predicted by genetic
diagnosis. However, making any progress in this direction
will be no simple matter.
Since personalized medicine means preparing drugs forpatients individually, it means an inevitable increase in thenumber of different types of drugs, as well as having to findout information on patients’ gene and protein expression inadvance. From a business perspective, this level of diversity
may run contrary to efficient research and development.
There is also concern that it will increase expenses for thepatient. Doctors in particular may face an increased weightof responsibility.
This idea will require diagnostic drugs and treatment
drugs to be developed together from early in the exploratory
stage. In Japan, these are separate industries and are still at
the trial-and-error stage. Although this has been trialed since2000 by Mitsubishi Chemical Holdings, a groupencompassing drug discovery, diagnostic drugs and clinicaltesting operations, the road ahead is anything but smooth.
Another fundamental issue is whether specifically-limited
biomarkers alone can identify people as responders (people
for whom the drug has medicinal efficacy) or non-responders(people with no reaction to the drug), due to the fact thatmultiple enzymes and receptors are involved in causing
diseases and in drug metabolism. The same is true for side
effects.
It is difficult to develop a drug that will be effective foreveryone, regardless of individual differences; however,personalized medicine also presents huge barriers. In Japan,
the Japan Pharmaceutical Manufacturers Association
established the Japan Pharmacogenomics Consortium (JPG
Consortium) in 2003, with 11 member companies taking part.
Some results were seen from a clinical pilot trial exploring
the SNPs involved in aspirin resistance, but there has been
little development since (24).
While Japanese drug discovery companies are taking noteof FDA policies, they are approaching those policies withcaution. However, other matters outlined in the Critical Path
Initiative are already known to Japanese drug discovery
companies through their own experiences. Companies willcontinue to use their own experiences in future developments
in drug discovery (25).

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March[3] Ordinance on Standards for Non Clinical Studies
Note 1: Target discovery generally refers to determining the point of action(target) of a drug; the discovery of targets in genomic drug discovery is often

concerning Safety of Pharmaceuticals (Ordinance of the
Ministry of Health and Welfare No. 21 of March 1997).

termed as target discovery.

[4] Kuranami J.: Yakuri Shiken to GLP no Kongo no Tenbō
Note 2: Innovative new drugs, or blockbuster drugs, have recently been

(Future Prospects of Pharmacological Tests and GLP).

referred to as “first in class”. Improved drugs with superior properties are

Folia pharmacologica Japonica 139:109-112 (2012).

referred to as “best in class”. While it is important to try to produce[5] Nagami K.: GLP towa Nani ka Sono Gaiyō to Tekiyō

blockbuster drugs, both to advance science and to prove the instincts ofresearchers correct, improved drugs are very significant in that they resolve

Han-i (What is GLP? Outline and Scope). Folia

issues found in prior products in terms of side effects and medicinal efficacy.

pharmacologica Japonica 130:403-407 (2007).

In many cases, it is the improved drugs that experience growth on the market
and are administered widely to patients.

[6] Amano H.: Kusuri no Rekishi (History of Medicine).
Yakuji Nippo 176-177 (2000).
[7] Hiyama Y.: Iyakuhin no Hinshitsu Kakuho to GMP

Note 3: The International Union of Pure and Applied Chemistry (IUPAC)
defines a pharmacophore as “the ensemble of steric and electronic features thatis necessary to ensure the optimal supramolecular interactions with a specificbiological target structure and to trigger (or to block) its biological response”.

(Quality Assurance of Pharmaceutical Products and
GMP). Bulletin of National Institute of Health Sciences
128: 1-16 (2010).

This concept is not new; it was proposed by Ehrlich in 1909.

[8] Sakakibara T.: Chiken-yaku GMP ni Tsuite (About GMP
Note 4: Pharmacokinetics: Drugs enter the body through various methods ofadministration (administration), are distributed within the body (distribution),
are metabolized by the body (metabolism) and are eventually excreted fromthe body (excretion). This sequence is referred to as ADME. Ideally, drugsof Investigational Drug). Folia pharmacologica Japonica
139:170-173 (2012).
[9] Takezawa M.: Rinshō Shiken no Jisshi no Kijun (GCP)

maintain their medicinal efficacy by remaining in the body for a certain length(Criteria for Conducting Clinical Trials (GCP)). Folia

of time, have no metabolite toxicity and are promptly excreted from the body

pharmacologica Japonica 138:205-208 (2011).

after serving their purpose.

[10] The human genome: Nature 409: 745-964 (2001).

Note 5: The International Genome Sequencing Consortium started in 1990

[11] The human genome: Science 291: 1145-1434 (2001).

with the participation of the United States, Japan, the United Kingdom,[12] Liang P, Pardee A. B.: Differential display of eukaryotic

Germany and other countries. In June 2006, US President Bill Clinton andmessenger RNA by means of the polymerase chain

British Prime Minister Tony Blair announced the results of the decoding at apress conference. Private venture Celera Genomics, led by John Craig Venter,
was opposed to the international project and fierce competition ensued to gain

reaction. Science 257: 967-71 (1992).
[13] Graduate School and Faculty of Pharmaceuticalprecedence in the field. In February 2001, the international project team

Sciences, Kyoto University: Atarashii Kusuri wo Dōpublished the genome sequence in Nature, while Celera Genomics publishedTsukuru ka (How to Create New Medicine). Kodansha

its own results in Science. The complete version was made public in 2003,
comprising 99% of the human genome sequence with 99.99% accuracy.

61-70 (2009).
[14] FDA: Development of New Stereoisomeric Drugs. May

Note 6: The optimization of candidate compounds has conventionally beenachieved by medicinal chemists using a mixture of experience, hard work,(1992).
[15] R. Kikumoto, Y. Tamao, S. Okamoto et. al: Selective

intuition and luck. While there are hopes that computer theory and the latest
advances in technology will be put to good use in optimization, newInhibition of Thrombin by (2R,technology alone does not necessarily mean perfect drug discovery and the4R)-4-Methyl-1-[N2[-(3-methyl-1, 2, 3,role played by medicinal chemists is as important now as it ever was. The

4-tetrahydro-8-quinolinyl)sulfonyl]-L-arginyl]]-2-piperi

success probability of producing a single drug is the topic of much discussion.

dinecarboxylic Acid. Biochemistry 23: 85-90 (1984).

Although the use of robotized synthesis and compound libraries has rapidly
increased the number of compounds that can be tested (the number of samples),it does not mean that the success probability has increased; the capabilities of[16] R. Noyori and H. Takaya: BINAP: An Eﬃcient Chiral

Element for Asymmetric Catalysis. Account of Chemical
Research 23: 345 (1990).

medicinal chemists are as highly regarded as ever.

[17] HS Report No. 36: Genomu Iryō Sōyaku ni okeru
References

Infomatikusu no Dōkō (Trends in Informatics for[1] Jurgen Drews: Drug Discover: A Historical Perspective:

Genomic Medicine and Drug Discovery). Japan Health

Science 287: 1960-1964 (2000).

Sciences Foundation 56-66 (2002).

[2] Thierry Langer, Rémy D, Hoffmann: Pharmacophores[18] Ishikawa T. & Horie T. (eds.): Sōyaku Saiensu no

and Pharmacophore Searches Vol. 32 Wiley-Blackwell

Susume (An Encouragement of Drug Discovery).

(2006).

Kyoritsu Shuppan 143-173 (2002).
[19] R. W. Estabrook: Microsomal Electron Transport andSystematized Survey on the History of Drug Discovery with Technical Development

63

Cytochrome P-450 System: Methods in Enzymology 52:
43-418 (1978).
[20] HS Report No. 54: Kisei Dōkō Chōsa Hōkoku-sho[23] HS Report No. 59: Posutogenomu no Iyakuhin Kaihatsu
to Shindan Gijutsu no Shin Tenkai (New Developments
in Post-genome Drug Development and Diagnostic

Sentan Iyaku no Jitsugen ni Mukete (Regulatory Trends

Technology). Japan Health Sciences Foundation 83-89

Survey Report: Toward the realization of advanced(2007).

medicine). Japan Health Sciences Foundation 103-120(2006).
[21] FDA: Challenge and Opportunity on the Critical Path[24] M. Tamaoki: Perspectives on the current state ofpharmacogenomics in drug development.
Yakugakuzasshi 129: 135-145 (2009).

to New Medical Products. March (2004).

[25] HS Report No. 62: Sōyaku Purosesu no Kakushin he[22] FDA: Critical Path Opportunities Report. March

Mukete (Toward Innovation of the Drug Discovery(2006).

Process). Japan Health Sciences Foundation 1-57
(2008).

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National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

4

Detailed Discussion (Lifestyle-Related Diseases)

This chapter addresses lifestyle-related diseases andOther types of diabetes include gestational diabetes anddiscusses the history of new drug discovery for diabetes,

secondary diabetes caused by other diseases; however, these

hypertension, hyperlipidemia, hematologic malignancy andaccount for very small numbers of patients.

hyperuricemia from the postwar period to the present.

The cells in our bodies act in various ways to keep us

Although a great many other pharmaceutical products havealive, using glucose absorbed from the digestive system as an

been developed for other diseases as well, including

energy source. The blood glucose level in the body increases

antibiotics/antibacterials, central/peripheral nervous systemafter eating; the beta cells in the islets of Langerhans in the

drugs, circulatory system drugs, endocrine system drugs,

pancreas are activated by the high blood glucose levels to

anticancer drugs, osteoporosis drugs, renal disease drugs andrelease insulin. This action causes the glucose to be rapidly

sensory organ drugs, these will need to be discussed on

taken and used by the tissue cells (liver, muscles, fat cells,

another occasion.

brain, etc.), thereby lowering the blood glucose level. During
fasting, the body produces a certain amount of glucose, either

4.1 Medications for Diabetes

by breaking down the glycogen stored in the liver andconverting it into glucose or by synthesizing glucose

According to the 2011 Patient Survey, conducted every(gluconeogenesis) from amino acids, lactic acid and glycerol,

three years by the Ministry of Health, Labour and Welfare,and releases it into the bloodstream. Under normal insulin

the total number of diabetes sufferers (patients assumed to beconditions, the production of ketone bodies

receiving ongoing treatment) was 2.7 million (1.48 million(beta-hydroxybutyrate, acetoacetate and acetone; abnormal

males and 1.22 million females). The number of adults

glucose metabolism causes increased compensatory lipid

suspected to have diabetes could be as high as 9.5 million.

utilization and increased ketone body production) is

The production value of drugs classified as diabetes drugs

suppressed. During fasting, ketogenesis occurs, resulting in

has grown in a decade from ¥112.5 billion in 2003 to ¥225

metabolic acidosis. Hyperglycemia also triggers diuresis withbillion in 2012. According to the International Diabetes

concurrent Na+ and K+ loss, eventually resulting in a coma.

Federation (IDF), in 2012 there were 371 billion diabetes

As mentioned above, there are thought to be two potential

sufferers worldwide between the ages of 20 and 79; Japancauses for ongoing high blood glucose levels: (1) a shortage

ranked ninth with 7.1 million diabetes sufferers, behindof insulin from the pancreas, either by delayed timing in

China, India, the United States and other countries.

releasing the insulin or by an insufficient amount of insulin

There are two types of diabetes, according to thebeing released; (2) the insulin receptors and the subsequent

pathology. The first is called type 1 diabetes (previously

signal transduction not functioning properly despite theknown as insulin-dependent diabetes), in which the beta cells

presence of insulin (insulin resistance). The latter can also bein the islets of Langerhans in the pancreas are destroyed bycaused by the tissue reacting to the insulin. Postprandial

viral infection, autoimmunity or chemical substances. While

hyperglycemia, in which the blood glucose levels in the bodyit often occurs in young people between the ages of 10 andelevate only after eating, is an indication that the body is not

20, it has a low occurrence rate in Japan, accounting for only

secreting enough insulin; it is thought to be the first stage of

5% of all diabetes sufferers. Since the body does not produce

deterioration in pancreatic function. If tissue becomesenough insulin, insulin has to be supplied externally.

resistant to insulin whether it is in sufficient supply or not,blood glucose levels will remain elevated for longer. One

The other type is called type 2 diabetes; in addition to
genetic predisposition, onset can also be triggered bytheory proposes that since glucose reacts easily with certain

overeating, lack of exercise and stress. It is thought to beamino acids in some peptides and proteins, prolonged

caused by either (1) insufficient insulin from the pancreas or

periods of elevated blood glucose levels will cause a(2) insufficient insulin action due to deterioration in insulin

glycation reaction (Maillard reaction), during which thereceptor function in the muscles and liver. Onset frequently

proteins in various cells in the tissue will degenerate.

occurs in people who gain weight in middle age; almost all

The glycation reaction forms chains, ultimately producing

instances (95%) of diabetes at the present time are this type.

advanced glycation end products (AGEs). While this is not

Insulin has been administered as a specific medicine toyet fully understood, there are reports indicating that AGEs

sufferers of type 1 and type 2 diabetes since 1922.

bond to receptors for AGEs (RAGEs) and cause various

Improvements continue to be made to insulin injections.

impairments. The degenerated proteins are the cause of three

Systematized Survey on the History of Drug Discovery with Technical Development

65

major complications, namely diabetic neuropathy, diabetic
retinopathy and diabetic nephropathy, as well as causing

Microangiopathy

arteriosclerosis in major blood vessels and causing heart

Retinopathy

Macroangiopathy

Cerebral
infarction

attacks and strokes. The glycation reaction due tohyperglycemia also increases susceptibility to infection bycausing abnormalities in immune cells. The diabetes

Inside thebodyNephropathy

Neuropathy

Intermittent claudication

Infection due to lowered
immunity

Fig. 4.1 Complications of Diabetes.

Receptor

Incretins

Digestive tract

Outside thebodybiomarker is glycated hemoglobin HbA1c (see Figure 4.1).
Hypoglycemia, the reverse of hyperglycemia, often occurs
in conjunction with pharmacotherapy for diabetes. People
who take insulin injections or hypoglycemic drugs during
treatment can experience hypoglycemia if they engage instrenuous activity, skip a meal, or if they accidentally
overdose on their medication. Hypoglycemia causes a variety
of symptoms, which can also include anything from a loss of
consciousness to a coma; accordingly, proper care must be
taken (1, 2, 3). Figure 4.2 shows the operation of insulin andblood glucose in the body.

Myocardial
infarction

Beta cells

Insulin
GlucoseMetabolism

Promotes glucose uptake
Gluconeogenesis inhibition

Urine

Liver / muscles / fat cells

Transporters
Source: Umezu 2014

 Blood glucose is controlled by insulin.
 Glucose absorbed into the blood from food is taken in by the tissue (liver, muscles, fat cells, brain, etc.) as anenergy source.
 During this time, insulin promotes “migration to tissue” and “utilization of glucose within the tissue”.
 Hyperglycemia is sensed and insulin is secreted by the beta cells in the pancreas. Incretins are secreted from thedigestive tract as hyperglycemia is sensed and promote insulin secretion in a different process.
 Glucose excreted from the blood into the urine is reabsorbed in the uriniferous tubules and returns into the blood.
- show the points of action of diabetes drugs.
 SU drugs and glinide drugs act on the beta cells to promote the secretion of insulin.
 Insulin sensitizers (biguanides, thiazolidinediones) act on the liver and other tissues.
 Glucose absorption inhibitors (voglibose) inhibit glucose absorption from the digestive tract.
 Incretins promote insulin secretion.
 Inhibiting incretin catabolic enzymes increases the efficacy of the incretins.
 SGLT2 inhibitors inhibit the reabsorption of urinary sugar into the uriniferous tubules, thereby lowering theblood sugar level.

Fig. 4.2 Operation of Insulin and Blood Glucose.

66

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchWhile lifestyle-related diseases have gained more
attention in recent times, there are few records of them fromancient times. However, diabetes is one such disease forwhich ancient records exist from various different regions.
The Ebers Papyrus, which dates back 3,500 years, records
a disease that causes “excessive urination”. In Japan, Shōyūki,
the journal of Fujiwara no Sanesuke, appears to record thatFujiwara no Michinaga died from diabetes. Michinaga’s
condition is described as “having constant dryness in themouth, feeble and drinking much water,” “emaciated in the
body and lacking strength,” “tumors forming on the back”
and “unable to see” (4). This is thought to be a good
representation of the characteristics of diabetes.
On a side note, Shōyūki also records in the fifth month of1016 that “Yorihide said that the death of Michinaga may be
imminent” (4).
It seems to have been known since ancient times that a
disease producing glucose in the urine was caused byinsufficient exercise and excessive dietary intake. However,it was not until 1922 that insulin was discovered by Banting
et al., while low-molecular-weight drugs to combat diabetes
did not emerge until the mid-20th century.
The Story of Insulin states, “Can diabetes be prevented orits commencement postponed in prediabetics? Not all
prediabetics go on to develop diabetes. We cannot answer
this question at the present time.” By the standards of
medical and pharmaceutical sciences at the time in the 1940s,
there would have been much that was yet unknown regarding
the prognosis for diabetes (5).
In 1947, glucose tolerance tests were carried out on 3,516
residents of Oxford, Massachusetts in the United States dueto the similarity of the age demographics of the town to thoseof New York. The study found that 70 people, or 2% of thesubjects, were diabetic; as many as half of them were
unaware of their diabetes. A further 118 subjects (3.5%)
made up the pre-diabetic group. Following this, similar tests
were carried out in various different countries around theworld; it was estimated that around 1-1.5% of Americans andCanadians had diabetes at that time. With diabetes patients inJapan accounting for 2.1% of the population in 2011 andassuming the number of presumed diabetes sufferers to be
7.3% (mentioned above), it is surprising how many diabetes
sufferers there were in the developed countries, even justafter the war, when the food situation would have been
unfavorable (5:184-189).
Although The Story of Insulin, published in 1962,
discusses the history of insulin in detail, it does not mention
any research on the action mechanism of insulin at molecularlevel. While it was known at the time that type 2 diabetes isrelated to weight and genetics and that there were patientswith prediabetes, it was not until the advances inbiochemistry and molecular biology in the 1980s that
research on insulin receptors, their signal transduction andtheir connection to blood sugar levels began to accelerate.

In 1988, Gerald Reaven proposed the theory that thelifestyle diseases of obesity, hypertension and diabetes werecaused by insulin resistance and poor glucose tolerance,
leading to cardiovascular disease (Syndrome-X) (6).
The following year, Norman Kaplan named thesynergistic deterioration effect of obesity (upper-bodyobesity), glucose intolerance (diabetes), hypertriglyceridemia(hyperlipidemia) and hypertension as “the deadly quartet” (7),triggering a wealth of research on insulin-resistancesyndrome. In 1998, the WHO published the diagnostic
criteria for what it termed “metabolic syndrome”; thissyndrome has become widely known, even in Japan.
Since 2008, the Ministry of Health, Labour and Welfare in
Japan has required medical insurers to carry out specifichealth examinations and provide specific health advice foraround 52 million medical insurance subscribers and theirdependents, between the ages of 40 and 74, with specificfocus on metabolic syndrome. Simple tests, such as blood
sugar, fat, blood pressure and girth, are used identify
pre-metabolic syndrome individuals, who are then given
advance health advice to maintain good health, thereby
reducing medical expenses.
However, the implementation rate has been lower thaninitial predictions, at 38.9% in 2008 and 46.2% by 2012. Of
all those tested in 2012, 17.7% were targeted to be given
specific health advice, while only 16.4% actually received
that advice. While the number of people being medicallyexamined each year is increasing, the general population still
remains largely unaware of metabolic syndrome.
4.1.1.

The History of Insulin as a Medicine

Insulin for diabetes has been a wonder drug (mentioned
previously). In 1923, Eli Lilly & Co. began mass producing
insulin from bovine and porcine pancreases; subsequently,
production began in countries around the world. Early insulin
formulation required refining due the presence of impurities;
however, this presented a paradox in that the more it was
refined, the more effective the medicine, but the shorter theeffective working time. This was because the impurities
prevented the insulin from breaking down. Accordingly,
research began on how to make insulin effective for longer,
eventually resulting in the discovery in 1936 by Hans
Christian Hagedorn that protamine, a protein isolated fromfish sperm, could be used to prolong the effectiveness of
insulin. In 1938, D. A. Scott and A. M. Fisher of Canada
reported that the effectiveness of insulin could be prolonged(hypodermic injection twice a day) if the insulin was mixed
with protamine as well as the zinc used for insulin
crystallization. It was found that by adjusting the ratio of zincand protamine, the period of effectiveness could be extended
from seven hours to three days. This PZI formulation became

Systematized Survey on the History of Drug Discovery with Technical Development

67

extremely widely used, thus improving insulin treatment.

Consequently, studies began on “insulin analog formulations”

This principle is still used today (5:96-103).

with slightly modified amino acid sequences.

However, when it was applied clinically, many patients

Ultra-fast-acting insulin analog formulations, which took

became hypoglycemic from the PZI regime. Doctors needed

effect even more quickly than the fast-acting formulations,a form of insulin somewhere in between the fast-acting

were released by Eli Lilly & Co. in 1995, by Novo Nordisk

crystalline insulin and the prolonged-effectiveness of PZI.

in 1999 and by Aventis (now Sanofi) in 2004 (10).

Various formulations were devised; Louis Bauman of the

Meanwhile, devices were being developed to

Wellcombe Trust developed globin insulin in 1939. Red

self-administer insulin. The pen-type insulin syringe emerged

blood cell globin combines with insulin to produce an

to combat the inconvenience of carrying around big syringes

intermediate-acting preparation. In 1945, Meller et al. of

every day. In 1985, Novo Nordisk launched the world’s first

Novo developed a formulation that did not contain any

insulin pen, with the insulin formulation held in a cartridge

proteins other than insulin (Lente insulin). In 1946, Hans

loaded into the pen, and the needle being the only

Christian Hagedorn developed NPH insulin with a reduced

non-reusable part (launched in Japan in 1988). It looked justamount of protamine. Research on the effectiveness period oflike a pen. The user would attach the disposable needle to theinsulin has continued since then to the present, with various

pen, insert the needle under the skin and then press thedifferent formulations being devised and developed. In 1978,

injection button once to administer two units of insulin into

Arthur Riggs and Keiichi Itakura used advanced genetic

the body. This dramatically increased its portability andengineering technology to successfully produce

greatly reduced the inconvenience associated with injections.

human-identical insulin from E. coli. In 1985, Eli Lilly

At present, each insulin formulation manufacturer isstarted selling insulin produced from E. coli, while Novo

marketing its own self-administered injection device, with

Nordisk did the same in 1987 with insulin produced fromvarious different syringes and improved modifications (Note 1).

yeast cells. These formulations improved the safety of insulin

While insulin treatment in Japan has progressed by means

treatment and also made it possible to start mass producing

of various different types of insulin from the West, it was not

insulin formulations (5).

until 1981, around 60 years after the discovery of insulin,

Meanwhile, according to A 50-year History of New Drugs

that patients were granted legal approval to inject their own

in Japan by Hikaru Ozawa (9), insulin was in wide use frominsulin. Although self-administration of insulin by patientsaround the middle of the Second World War and into the

had been a matter of course in the West since insulin was

postwar era (1940-1956), being produced by Shimizu

first discovered, it seems that it was harder to accept in Japan,

Seiyaku from Katsuwonus pelamis, Thunnus orientalis andamidst apprehension about patients administering injections

other bony fish, which were abundant in supply in Japan.

with no medical qualifications.

The entry for “insulin injections” in the sixth revision of the

Despite Keiichi Itakura et al. at the American

Japanese Pharmacopeia (1951) describes it as an “aqueous

biotechnology venture Genentech successfully producing

solution containing a hypoglycemic ingredient from thehuman insulin by genetic engineering in 1978, it was Eli

Langerhans cells of edible animals or fish”. The introduction

Lilly, Novo Nordisk and other conventional Westernof long-acting insulin formations developed in the West

corporations that led the world in the technology for

during the war was somewhat delayed, with import approvaladministering insulin to patients; unfortunately, Japanesegiven for protamine zinc insulin in 1951, for globin zinc

drug discovery companies trailed behind in this arena (11).

insulin in 1952, for NPH insulin in 1955 and for Lente
insulin in 1956.
The next step in insulin development was the development

However, with many patients finding self-administeredinjections inconvenient, research was also continuing onorally administered drugs. Japanese drug discovery

of insulin that was more physiologically effective. While thecompanies in particular were achieving results from theirinsulin secreted from the pancreas is a monomer, thededicated research and development of oral diabetes

fast-acting insulin was a hexamer that was highly stable inmedications.

formulations. When the fact-acting insulin was injected, it
broke down from a hexamer into dimers and monomers andwas transported throughout the entire body in the
bloodstream. Since it took around 30 minutes to come into
effect, it had to be injected around 30 minutes before eating.
Meanwhile, the insulin formulations with additions
protamine and zinc to prolong the effectiveness circulated
through the body in fixed amounts 24 hours per day; these in
no way imitated the natural insulin secretions of the body.

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National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

4.1.2.
Sulfonylurea (SU) Oral Diabetes Medications
In 1942, Marcel Janbon discovered that one of the sulfa
drugs used in clinical studies for typhoid fever contained acompound that had a hypoglycemic effect (12). This
compound became the first sulfonylurea oral diabetes drug.
On learning this, many chemists started screening in order tosynthesize analogous compounds. This resulted in thesynthesis of sulfonylurea drugs Carbutamide in 1955 andTolbutamide in 1956, still used today, by German companies
Boehringer Mannheim and Farbwerke Hoechst. Another SU
drug, Glibenclamide, emerged in 1969. Glibenclamide is alsoa sulfonylurea drug and was selected from among around
8,000 similar hypoglycemic compounds out of consideration
for its efficacy and level of toxicity.
Around this time, it was reported that new oral diabetes

drugs were ineffective against type 1 diabetes and ineffective
against serious cases of type 2 diabetes. Tolbutamide waslater shown to have a mechanism of action of stimulating thepancreas to release insulin, thereby showing Tolbutamide to
be ineffective when the pancreas is not working properly,
such as with type 1 diabetes.
Recent research has proposed an arrangement in which thesulfonylurea (SU) receptors exist alongside theATP-sensitive K+ channel on the membrane of the beta cellsof the pancreas; when SU derivatives bind to the SU
receptors, which form part of the K+ channel, the K+ channel
closes and depolarization occurs, whereupon the calcium
channel on the membrane opens accordingly and Ca2+
(calcium ions) flow into the cells from outside, resulting inthe secretion of insulin (see Figure 4.3) (13).

SU drugs
Glinidedrugs
GlucoseSU receptor

K channel

TCA cycle
GLUT2 receptor
Amplification

Ca channel

GLP-1 receptors

InsulinBreakdown

Source: Umezu 2014

The detailed mechanism of action of diabetes drugs in relation to the release of insulin from thebeta cells is now becoming clear.
A: Glucose stimulation route
B: Incretin stimulation route
C: SU (sulfonylurea) receptor route- show the points of action of diabetes drugs on the beta cells in the pancreas.

Fig. 4.3 Beta Cell Insulin-Releasing Drug Mechanisms.

Systematized Survey on the History of Drug Discovery with Technical Development

69

The first generation of SU drugs to be developed(Tolbutamide, Acetohexamide, etc.) had low potency andhad to be administered in high volumes to be effective fortreatment; however, administration in high volumes caused
hypoglycemia. SU drugs were also problematic in terms ofinteractivity, in that they bonded strongly with albumin in the
blood. The second-generation drug Glibenclamide wasintroduced to Japan by Hoechst in 1971 and marketed by
Chugai Pharmaceutical (14). Gliclazide was introduced byServier in 1984 and marketed by Dainippon Pharmaceutical(now Dainippon Sumitomo Pharma). These were morepotent than the first-generation drugs and also had lower
interactivity with other drugs due to their nonionic bonding
properties with blood albumin. Glimepiride (Sanofi-Aventis),which emerged in 2000, is called a third-generation drug, as
it works despite poor insulin secretion, its hypoglycemic
effect is equal to or better than other SU drugs and it isthought to reduce blood sugar levels by acting outside of thepancreas (promoting glucose use in the muscles andinhibiting glucose release from the pancreas) (15).
Having noted the insulin release effect, Japanese drug
discovery companies have focused on research anddevelopment of “fast-acting insulin secretagogues”, which
enhance this effect. These “fast-acting insulin secretagogues”
could be called the fourth generation SU drugs, and they
have their origins in Japan (16:25) (mentioned later).
While SU drugs are often used together with insulin, side
effects can include susceptibility to hypoglycemia or an
increase in body weight.
In 1970, the results were published for the University
Group Diabetes Program (UGDP), a large-scale clinical test
on major SU drugs for side effects (17). The results showed a
75% increase in cardiovascular deaths in the Tolbutamide
treatment group over the placebo group; the use of SU drugs
decreased amidst the ensuing debate on SU drug usage. A
number of other tests were carried out; the United Kingdom
Prospective Diabetes Study (UKPDS), a large-scale clinical
trial conducted from 1977 to 1991 (Note 2), dismissed the
hypoglycemic effect of SU drugs and the risk cardiovasculardeath (18). Nevertheless, results of othersmall-to-medium-scale tests have confirmed these risks,meaning that further research is still needed.
4.1.3.
Fast-Acting Insulin Secretagogues
Japanese characteristically have lower insulin secretion
capacity than Westerners; there are many cases of people
with abnormal glucose tolerance whose release of insulin
after eating is at a slower rate than the elevation in theirblood sugar level. Glinides were developed specifically for
the Japanese in order to combat this issue. These drugs arecharacteristically fast-acting, thereby having the effect ofincreasing insulin secretion within a short space of time. The
concentration in the blood peaks within 30 minutes to 2
hours before being metabolized by the liver and thenpromptly excreted from the kidneys. This characteristically

70

short period of effect is close to the normal insulin secretion
pattern. In recent years, studies both in Japan and overseas
have reported that postprandial hyperglycemia is anindependent risk factor for causing diabetes-related vasculardiseases (19).
The idea of preventing postprandial hyperglycemia led to
the release of a succession of Japanese products, such as
Nateglinide by Ajinomoto in 1999, followed by Mitiglinide
by Kissei Pharmaceutical in 2004. This drug was morepotent than Nateglinide, but without the side effect of
postprandial hypoglycemia. Repaglinide was launched on themarket in 2011 by Dainippon Sumitomo Pharma throughNovo Nordisk.
The pharmacological effect of glinides is reported as
inducing depolarization by binding to sulfonylurea receptor
subunits in the ATP-sensitive K+ channel to inhibit the K+
channel and ultimately induce insulin secretion (20). Since
these have a less potent effect than SU drugs, they aresuitable for mild type 2 diabetes patients with postprandial
hyperglycemia. It should be noted that because they are afast-acting insulin secretagogue, they have no effect unlessthey are used directly before eating and that they cannot be
used in combination with other SU drugs with the same
effect. Their characteristically short period of effect is close
to the normal insulin secretion pattern.
Figure 4.5 shows the chemical structural formulas ofdifferent generations of typical sulfonylurea drugs.
4.1.4.
Biguanides
Although C. K. Watanabe of Japan had reported in 1918
on observing a blood glucose effect in guanidine, theforerunner of the biguanides, this was overshadowed by the
epoch-making discovery of insulin in 1922 and medical
research shifted from that path. It was not until around 1961
that the biguanide Metformin gained a foothold as an oral
diabetes medication. In the 1970s, there were lactic acidosis
issues with Phenformin, another biguanide, resulting in the
maximum administration dosage of metformin being halved.
Limitations were placed on its indications and it became
poorly rated. The results of the University Group Diabetes
Program (UGDP), a large-scale clinical trial for SU drugs
and biguanides, were also reported at the end of seven yearsof treatment (17, 21). These results showed an increase insignificant deaths among the SU drug Tolbutamide groupand the biguanide Phenformin group over the control group;
amidst growing apprehensions, biguanides and SU drugs
declined in use.
It was later reported that Phenformin was the only
biguanide to cause lactic acidosis. The double-blind
Multicenter Metformin Study (1995) conducted in the UnitedStates reported that Metformin was very beneficial for type 2
diabetes accompanying obesity. The Diabetes Prevention
Program (2002) also concluded clear vascular event
inhibitory effects and diabetes onset prevention effects. On
the basis of such results, the safety and utility of Metformin

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchbegan to be reconsidered. While the UKPDS also
demonstrated that patients administered with Metformin
showed improved cardiovascular prognosis (18), it took
almost another 30 years for the era of lactic acidosis
apprehension to finally come to an end.
Currently, Metformin is often used in conjunction withinsulin due to its low potency on its own; however, there aresometimes issues with hypoglycemia due to concomitantadministration.
The main pharmacological effects of biguanides takeplace outside of the pancreas. For example: (i) inhibiting therelease of glucose by inhibiting gluconeogenesis in the liver;(ii) boosting the uptake and utilization of glucose by theskeletal muscle and the fat cells; (iii) lowering the rate ofabsorption of glucose from the digestive tract, thereby
improving insulin resistance. Another importantcharacteristic is moderate improvement in hyperlipidemia(2:368-369).
Into the 21st century, there have been many reports on the
progress of research on detailed mechanisms of action atmolecular level. These findings include increasing thecellular AMP/ATP ratio by inhibiting the mitochondrial
respiratory chain complex I, thereby increasing theintracellular AMP to activate the AMP-activated protein
kinase (AMPK) and thus improve the glucose metabolism, as
well as stimulating GLUT4 transporter migration to the cell
membrane and inhibiting the action of glucagon (21, 22).
4.1.5.
Alpha-Glucosidase Inhibitors (α-GIs)
The sulfonylurea drug Tolbutamide went onto the market
in 1957, followed by the biguanide Metformin in 1961;
however, no further “new mechanism” oral diabetes drugs
emerged for quite a long time after that. Although various
companies continued research and development on new
diabetes medications out of concern over the side effects of
SU drugs and biguanides, it was quite some time before any
new drugs hit the market.
Three decades later, in 1993, the α-glucosidase inhibitor
Acarbose (Bayer) finally came onto the Japanese market,
followed by the domestic product Voglibose the following
year in 1994 by Takeda Pharmaceutical. A succession ofother insulin sensitizers started being put into clinical use,
including thiazolidines Troglitazone and Pioglitazone andfast-acting insulin secretagogues (glinides) Nateglinide and
Mitiglinide. The research and development by Japanese drug
discovery companies was finally starting to make somenoticeable headway.
While glucose metabolism in the body is usually whatcomes to mind in relation to diabetes and insulin, the idea of“α-glucosidase inhibitors” is completely different.
Carbohydrates are present in food in forms such aspolysaccharide starch; these are broken down into
oligosaccharides including disaccarides, mostly by theamylase in the saliva and secreted from the pancreas. The
disaccharides are then broken down further into glucose by
the α-glucosidase (an enzyme group rather than a specificenzyme, including maltase, sucrase and otherdisaccharidases) present in the small intestinal mucosa. The
glucose is transported within the body by glucose
transporters, which are unable to transport oligosaccharides
or starch. If an inhibitor were to completely inhibit
α-amylase and α-glucosidase, no glucose would be absorbed
into the body. Since these do not actually block these
enzymes 100%, glucose is transported within the body insmaller amounts or at a delayed pace. This creates similar
conditions to dietary restrictions by using medication. While
experiments on animals have confirmed the validity ofblockers, there have been concerns about side effects in thegastrointestinal tract caused by undigested carbohydrates. In
fact, Acarbose did cause gastrointestinal side effects,
including flatulence, bloating and upset stomach.
Bayer’s Acarbose tablets came in 50 mg and 100 mg sizes,
while the dosage for the domestically-produced Voglibose
was far lower at 0.2 mg and 0.3 mg, which was expected to
improve the issue of side effects. Following clinical testing,Takeda Pharmaceutical launched Voglibose on the market
one year after Bayer’s product. It was used by postprandial
hyperglycemic diabetics whose “blood glucose levels did notelevate significantly during fasting, but elevated rapidly after
eating”. The results were favorable; although there weresome complaints of the digestive tract as feared, these were
not enough to negate the main medicinal efficacy of the drug.
Takeda Pharmaceutical’s History of Innovative Researchand Drug Discovery at Takeda provides some informationon the development history of Voglibose (23). Basic researchbegan at in 1973 at the Takeda Pharmaceutical laboratory
with the aim of producing an anti-obesity agent. The idea
was to create “a drug to curb obesity” by inhibiting theabsorption of sugar. This was more than a decade before
metabolic syndrome became the focus of attention.
The news that German company Bayer had alreadyembarked on an α-glucosidase inhibitor project anddiscovered the blocker Acarbose (brand name Glucobay®)from culture filtrate in 1977 prompted Takeda
Pharmaceutical to launch a full-scale project in its ownlaboratory.
Screening the compound bank and culture filtrates while
taking hints from the structure of Acarbose resulted in the
discovery of candidate compounds in 1981. Voglibose was
eventually selected from the analogs that were synthesized.
At the time, biological laboratories were using pathologicalanimal models in their research to test their anti-obesity
agents. New animals, such as KKAy mice and Wistar fatty
rats, were developed as new disease models for obesity anddiabetes (see Section 4.1.6 below). Non-obese diabetic rats
(streptozocin-administered rats) were also developed tomanifest pathology similar to the Japanese. These models
were used to demonstrate that Voglibose had an anti-obesity
effect six to eight times greater than that of Acarbose, as well
as a pancreas protective effect. Having a number of these
independently-developed animals could be said to havecontributed significantly to research and development.
Comparative studies on the medicinal efficacy of
Voglibose and Acarbose revealed that while Voglibose at

Systematized Survey on the History of Drug Discovery with Technical Development

71low doses strongly inhibited blood glucose level elevation in
animals given starch and disaccharides, it did not inhibit
blood glucose level elevation in animals given
monosaccharides or lactose. Meanwhile, Acarbose wasconfirmed to be 3,400 times more powerful than Voglibose
at inhibiting amylase, resulting in undigested matter being
excreted in the feces. This was because Voglibose had a very
powerful α-glucosidase-specific inhibiting effect.
Later, when it came to the domestic phase 1 clinical trial
stage of testing on healthy individuals, an issue arose withpotential liver cell damage, with indicated elevated levels of
liver function indicators aspartate aminotransferase (AST,
identical to GOT) and alanine aminotransferase (ALT,
identical to GPT). However, Takeda’s central researchlaboratory hypothesized that “enzymes had escaped from theliver cells as a result of protein glucose production
mechanisms being activated due to slow glucose absorption”.
The hypothesis was proven correct when the administrationof Voglibose to rats on a high-protein diet inhibited theescaping enzymes.
Although obesity was the top application for Voglibose at
the time, development of it as an anti-obesity agent had to bediscontinued after severe abnormal abdominal symptoms
manifested in a pre-phase 2 clinical trial pilot study inEurope.
Clinical studies later continued with the dosage reduced,
the testing protocols modified and the target for the drug
amended to “improving diabetic postprandial
hyperglycemia”. This was more effective than anticipated;
thus, the new-concept postprandial hyperglycemia inhibitor
Basen® came into being. This success was probably due to(i) the change in clinical indication, but mostly (ii) the skillof the research team at Takeda in developing their own
various kinds of pathological animal models for diabetes andobesity at the basic research stage (24, 25). Figure 4.4 shows
the mechanism of action of α-glucosidase inhibitors, while
Figure 4.5 shows the chemical structure.
4.1.6.
Thiazolidine Derivatives (Insulin Sensitizers)
Diabetes is not only caused by insulin deficiency; it canalso be caused by the loss of signal transduction by theinsulin receptors in the liver, muscles or fatty tissue,
regardless of whether or not enough insulin is being secreted,resulting in no glucose utilization and, consequently,
hyperglycemia. This is known as “insulin resistance” and is a
cause of metabolic syndrome.

StarchSucroseα-glucosidase
MaltoseSucraseMaltaseGlucoseFructose

Source: Umezu 2014








Gastrointestinal blood vessel

Starch is metabolized into maltose by α-glucosidase and then into glucose by maltase, and then absorbed into the body.
Sucrose is metabolized into glucose and fructose by sucrase, and then absorbed into the body.
Sucrase and maltase are α-glucosidase enzymes that metabolize disaccharides.
When α-glucosidase is inhibited, the absorption of monosaccharides is inhibited.
When amylase is inhibited, starch is excreted from the body without being metabolized.
Compared to Acarbose by Bayer, Voglibose by Takeda (i) specifically inhibited α-glucosidase, and (ii) was not absorbed by the body. As aresult, there were fewer side effects such as diarrhea; another significant feature was that since it was not absorbed, there was no buildup of
hepatic glycogens and no inhibition of the lysomal enzymes of the liver.

Fig. 4.4 Mechanism of Sugar Absorption Inhibitory Action.

72

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchSU drugs and biguanides were the only diabetes drugs forquite some time; there were no diabetes drugs emerging withany new mechanisms of action. When Ciglitazone (Takeda
Pharmaceutical) reached the clinical stage in 1981, theconcept of “insulin-resistance-improving drugs” wasground-breaking. Many drug discovery companies, both inJapan and overseas, started competing to develop new drugs,
screening peripheral compounds and eventually embarking
on clinical trials. However, Ciglitazone lacked in medicinal
efficacy and its development was discontinued (1983). After
that, a succession of drug development companies also
discontinued their developments after encountering side
effects, presumably due to an issue with the basic
thiazolidine structure, which had been the basis for the
candidate compounds being developed. Drugs that made it as
far as the market included Troglitazone (released 1997) by
Sankyo, Pioglitazone (1999), developed by Takeda
Pharmaceutical almost in parallel with Thiazolidine, andRosiglitazone by GSK.
Let us now examine the history of research anddevelopment of “insulin-resistance-improving drugs”, aconcept that originated in Japan. While having started out asa ground-breaking idea, the history of this new drug
development has been one long battle against side effects. As
mentioned in Section 4.1.5. Alpha-Glucosidase Inhibitors
above, Takeda Pharmaceutical started out in the early 1960s
to develop anti-obesity agents and hypolipidemic agents,
with the bold new idea that “obesity underlies all
lifestyle-related diseases” (26).

SU drugs and glinides

At the time, pathological animal models for obesity did
not exist; however, the researchers at Takeda endeavored todevelop them, with the idea that these animals would beneeded in order to develop new drugs.
The diabetic KK mouse was produced by Nagoya
University in 1963. Pathophysiological studies on this mouseshowed a notable elevation in blood insulin concentration
when it was overweight, thereby revealing an “insulin
resistance” that lowered the effect of the insulin. This was at
a time when the concepts of “insulin resistance” and“metabolic syndrome” were still unheard of.
Hyperinsulinemia was successfully induced by means of
diet-controlled weight gain; this model corresponded to theprediabetes group in humans. However, due to the effort
required to achieve this pathology and the time it took tobuild up the required number of mice, the researchers at
Takeda decided to collaborate with Nagoya University tojointly develop spontaneous-onset mice. Researchers
introduced the obesity gene Ay to the KK mice throughbreeding and by 1967 had successfully developed KKAy
mice (mice with spontaneous onset of obesity and diabetes).
By 1974, a stable supply of these mice had been achieved for
antidiabetic drug screening. Efforts were also put intodeveloping pathological model rats, which were easier to use
in experiments. At the time, it was known that Kyoto
University’s spontaneously hypertensive “Wistar Kyoto rat”
was mildly insulin resistant. This rat was bred with thegenetically obese “Zucker fatty rat” to successfully produce
the obese, diabetic “Wistar fatty rat”.

Biguanides

First generation: Tolbutamide
Metformin

Second generation:
Glibenclamide
Introduced in 1961, but issues occurred with side effects. Laterreassessed and released by Dainippon Sumitomo Pharma in2010.
Third generation: GlimepirideFirst generation to third
generations drugs have a“sulfonylurea structure”

Alpha-glucosidase inhibitors
Acarbose: Bayer

Glinides: Nateglinide
Ajinomoto
Glinides do not have a SU
structure

Voglibose: Takeda
PharmaceuticalFig. 4.5 Chemical Structures of Representative Diabetes Drugs(1).

Systematized Survey on the History of Drug Discovery with Technical Development

73

These pathological animal models contributed
significantly not only to screening, but also to research on theside effect mechanisms of Pioglitazone (released 1999) andto clarifying matters on insulin resistance (26).
Screening was conducted using KKAy mice; of thecompounds synthesized using the hypolipidemic clofibrate as
the lead compound, AL-294 indicated powerful efficacy.
This was used to obtain the compound AL-321, with athiazolidinedione structure. Further derivatives weresynthesized, ultimately producing Ciglitazone, with acyclohexane ring in a side chain. Although Ciglitazone went
to clinical trial in the United States in 1981, it demonstrated
no medicinal efficacy; the trial was discontinued in 1983.
However, using the information that Ciglitazone
metabolism involves more powerfully active substances,compounds were able to be obtained that were five to eighttimes more active by replacing the Ciglitazone “cyclohexanering” with a hydrophilic substituent “pyridine ring”. One
such substance was Pioglitazone.
Around this time, Troglitazone by Sankyo also went toclinical trial and the competition grew fierce.
The “insulin sensitizer” Troglitazone was developed inJapan based on a completely different concept from
Pioglitazone. In 1980, Sankyo started full-scale research on“diabetes medications with insulin sensitivity enhancing
action”. The hypothesis was that various disorders werecaused by lipid peroxides, which increase in production in adiabetic state; in vitro screening commenced with the aim offinding a compound that would act to regulate the productionof these lipid peroxides.
Having tested several hundred synthetic compounds, thesynthesis team discovered the activity of CS-045, which has
a Vitamin E partial structure. When this compound wasassessed in vivo, it had no effect on regular mice. However,when administered into the feed of KK mice, theinsulin-resistant pathological animal models withcharacteristic hyperinsulinemia, the blood glucose levels andinsulin concentration in the mice was found to decrease
markedly. The compound went into preclinical testing in
1984. Although its absorption rate decreased as the purity
increased, greater absorption was achieved throughamorphization of the compound’s raw material to produce asolid dispersion with an irregular molecule arrangement. The
animal experiments confirmed the compound to have theground-breaking mechanism of action of reducing the blood
glucose level by promoting glucose utilization in the liver,muscles and fatty tissue. Joint clinical development began inJapan and the United States. Following the clinical trials, thedrug was launched simultaneously in Japan (Noscal®) andthe United States (Rezulin®) in 1997; it was also launched in
the United Kingdom (Romozin®) six months later. These
were the world’s first insulin sensitizers to be made available
on the market, even earlier than Pioglitazone.
Clinically, the drugs demonstrated superior efficacy inpatients who were secreting insulin but whose insulin was

74

functioning poorly. However, Troglitazone was voluntarily
recalled from the market in 2000 after some patients
presented with liver damage (27).
Meanwhile, Pioglitazone by Takeda Pharmaceutical was
jointly developed in the 1980s together with Upjohn (nowPfizer) in the United States. The results of clinical testing in
the United States in 1990 indicated that the drug lacked
adequate medicinal efficacy; Upjohn withdrew from theventure and development was suspended. However,following negotiation with the FDA and amendment of theclinical trial protocols, the clinical trials resumed in 1995. To
ensure safety, 20,000 clinical test cases were carried out.
Pioglitazone was later launched back on the market in Japanand the United States in 1999 and in Europe in 2000 (27).
The new idea of insulin resistance improvement using
pathological animal model selection became clear-cut in the
1990s. PPARα was discovered as a receptor that activatesperoxisome proliferation in the liver; its subtype PPARγ was
also discovered. It was found that thiazolidine derivatives area ligand (agonist) for these. Pioglitazone was found to act on
nuclear receptor PPARγ to promote adipocyte differentiationand conversion to small adipocytes, thereby increasing
insulin sensitivity and promoting glucose uptake. Reported
research results included inhibiting gluconeogenesis in theliver and muscles to lower the blood sugar levels,
administering Pioglitazone to reduce Tumor Necrosis
Factor-α (TNF-α), Interleukin-6 (IL-6) and otherinsulin-resistance-promoting adipocytokines, increasing theblood concentration of adiponectin, which has ananti-arteriosclerotic action, and improving vascularendothelium function for macrophages. Although the idea ofdrugs to improve insulin resistance originated in Japan withan innovative mechanism of action, it is unfortunate thatmost of the academic research was conducted overseas (27, 28,29).
With the mechanisms and testing methods made clear,more than ten Japanese drug discovery companies embarked
on research and development on insulin sensitizers, althoughvarious companies pulled out due to a lack of safetyassurance. In the end, the only thiazolidine derivatives left
were Rosiglitazone by GlaxoSmithKline (GSK) (marketed inEurope and the United States, but not in Japan) and
Pioglitazone by Takeda Pharmaceutical (marketed in Japan,
Europe and the United States).
Since these drugs worked to improve insulin resistance,
they had a fundamentally different mechanism of action from
SU drugs and insulin. Rather than lowering blood sugar
levels by taking a single dosage, they tended to lower the
insulin concentration. Meanwhile, it was also found that themechanism of action was related to increases in body weight;
since body fluids would accumulate, attention had to begiven to the burden placed on the heart.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchAlthough Rosiglitazone (GSK) was marketed in the West
as a superior diabetes drug, major issues were raised when

the pancreas.
After that came the discovery of the gastrointestinal

the results of a meta-analysis combining a number of tests
with different protocols (Note 3) were published by Stevehormone gastric inhibitory polypeptide (GIP) in 1969,
followed by the discovery of glucagon-like peptide 1

Nissen and Kathy Wolski in the New England Journal of
Medicine in 2007, entitled “Effect of Rosiglitazone on the(GLP-1) in 1983.
It was known that GIP is secreted by the K cells in the

Risk of Myocardial Infarction and Death from
Cardiovascular Causes” (30). Based on the meta-analysis, theupper small intestine, whereas insulin is secreted by thepancreas. Once it was found that under diabetic conditions

authors concluded that “until more precise estimates of the
cardiovascular risk of this treatment can be delineated in

GIP not only lacks adequate insulin secretion promotion
action, but also induces obesity by acting to promote fatpatients with diabetes, patients and providers shouldcarefully consider the potential risks of rosiglitazone in the

uptake by fatty tissue, drug discovery companies lost interestin GIP.

treatment of type 2 diabetes”. In response, GSK produced
past clinical test cases and strongly argued that a conclusion

Meanwhile, later research found that GLP-1 (apolypeptide made up of 29 amino acids in a particular 7-36

could not be reached on the meta-analysis results alone.
However, the attention drawn to the potential risk of heartsequence of peptides with an insulin-secretion promoting
action) directly acts on the beta cells in a glucose-dependent

disease became an issue for society and GSK took a 38%
drop in turnover.

manner to elevate c-AMP concentration and induce insulin
secretion, as well as acting on the alpha cells to inhibit

Ultimately, sales were discontinued in Europe, although
the FDA initially allowed the drug to continue to be used inglucagon secretion. While glucose promotes insulin secretionby the beta cells, the action of GLP-1 works as a “potentiator”

the United States with conditions in place; these conditions
were lifted in June 2013. However, GSK had taken a severe

to enhance the effect of Ca2+ in the insulin secretionmechanism. SU drugs are “initiators” that have the potential

hit.
Although Pioglitazone sales grew favorably in Japan andto cause hypoglycemia by inducing insulin secretion even in
the presence of low glucose levels; by contrast, incretins are

the United States as a promising new drug with a novel
mechanism of action and efficacy, patients in a clinical trial“potentiators” that do not promote the secretion of insulin
where there are low glucose levels and no elevation inin Europe (France and Germany) presented with bladdercancer in 2005. It was decided to include bladder cancer as a

intracellular Ca2+ concentration. Since they only promoteinsulin secretion when there is an elevation in intracellularrisk on the package insert (Note 4).
With the results of clinical studies in the United States

Ca2+ concentration, it can be assumed that they would notcause hypoglycemia (31). Research on GLP-1 as a drug has

showed the occurrence of bladder cancer as 6.9 per 10,000
Pioglitazone non-recipients (the control group) and 8.2 peraccelerated, with other recent findings showing GLP-1 toinhibit hyperplasia and cell death (apoptosis) in beta cells, as

10,000 Pioglitazone recipients, the FDA has approved thecontinued sale of Pioglitazone (April 2014).

well as inhibiting gastric emptying and appetite loss.
Since the polypeptide GLP-1 can be rapidly metabolized

In August 2014, Takeda Pharmaceutical reported its
ten-year epidemiological findings to the Ministry of Health,in the blood by the proteolytic enzyme dipeptidyl peptidase-4(DPP-4) at a rate of 95% within two minutes, only 5% or lessLabour and Welfare, the FDA and the European Medicines
Agency (EMA). According to that report, “the primaryof it reaches the original point of action, the pancreas.
Accordingly, improved analogs have emerged on the market,

analysis found no association between the use of
pioglitazone and the risk of bladder cancer”.

having been synthesized to be and less easily broken down
and to be administered by injection. Like insulin, the4.1.7.
Incretin-Related Drugs (GLP-1 Analogs)
Following the discovery of insulin, there was a theory that
substances other than insulin would lower blood glucose
levels; these substances were termed incretins. In 1964, it

injections are performed by the patient using a pen-typesyringe.
Liraglutide and Lixisenatide are GLP-1 analogs with someof the amino acids altered to become less easily broken down
by DPP-4. Exenatide (Eli Lilly) is a synthetic compound
produced using a 39-amino-acid peptide extracted from thewas reported that after administering glucose to healthy
individuals either orally or by intravenous injection toequalize their blood glucose levels and then measuring theirblood insulin concentration, those who had been
administered glucose orally had overwhelmingly higher
insulin concentrations. It was presumed that the digestive

Gila monster Heloderma suspectum to change the action sitein order to avoid the action of DPP-4. Interestingly, 53% of
this peptide found in the salivary gland of the Varanoidea
superfamily of lizards shares the structure of human GLP-1.

tract had some kind of mechanism for secreting insulin due
to glucose-related signal transduction from the beta cells in

Systematized Survey on the History of Drug Discovery with Technical Development

75

The product was released on the Japanese market in 2010,
imported from overseas. No domestic development wasundertaken; instead, Japanese drug discovery companies
entered the market by researching orally-administered DPP-4
inhibitors. This is characteristic of the Japanese medical
industry, which tends to avoid injected medications.
4.1.8.
DPP-4 Inhibitors
In 1994, DPP-4 was identified as the enzyme that breaks
down incretins. Research began on inhibitors for this enzyme,
as inhibiting DPP-4 would enable GLP-1 to survive longer inthe blood, thereby enhancing its insulin-secreting action.
Unlike existing medications, DPP-4 inhibitors promoted
insulin secretion in relation to glucose levels, thereby
preventing hypoglycemia and weight gain. Accordingly,
Sitagliptin, launched in the United States by Merck in 2007,
gained blockbuster status within three short years of its
approval. In terms of Japanese market trends in DPP-4
inhibitors, imported Sitagliptin was the first to hit the market
in 2009. Seven new players hit the market between 2010 and2013, with Vildagliptin (Novartis Pharmaceuticals) and
Alogliptin (Takeda Pharmaceutical) released in 2010,
Linagliptin (Boehringer Ingelheim Japan / Eli Lilly Japan)
released in 2011, Tenegliptin (Mitsubishi Tanabe Pharma)and Anagliptin (Sanwa Kagaku) in 2012 and Saxagliptin(Kyowa Hakko Kirin) in 2013. While the Japanese system
for new drug approval took longer than its Westerncounterparts, resulting in different release times, four of theseven new drugs were developed by Japanese companies, acommendable effort by the Japanese companies in the new
drug development competition, considering that theirstrengths lie in developing improved new drugs. Since theforerunner Sitapgliptin was a renally-eliminated drug
excreted in the urine through the kidneys, it could not readily
be administered to patients with renal diseases; thus, somedemand was noted for biliary-excreted DPP-4 inhibitors.
However, lowering the dosage of Sitagliptin made it suitablepatients with renal diseases and allowed it to leverage its
position of primacy in the market.
Although there are variations between the DPP-4
inhibitors in terms of dosage amount, dosage frequency,
excretion pathway, metabolic pathway and half-life in the
blood, the utility and side effects can only be revealed
through future results. When Japan was in the earlypost-marketing stage for DPP-4 inhibitors, an issue arosefrom a case report in which a disturbance of consciousness
was caused by serious hypoglycemia following the
supplementary administration of a DPP-4 inhibitor to a SU
drug.
To clarify and respond to the issue, the Japan Diabetes
Society established the “Committee for Proper Use of
Incretin and SU Drugs” and issued a recommendation
outlining proposed measures to be taken when concomitantly
administering SU drugs and DPP-4 inhibitors. The number ofserious hypoglycemia incidents has reduced since then. Fig.
4.6 shows the chemical structures of some representative
diabetes drugs.

Insulin sensitizers (thiazolidine)
New mechanism of action originated in Japan; issues
with side effects

Pioglitazone: Takeda Pharmaceutical

Rosiglitazone: GSK

DPP-4 inhibitors
Much involvement by Japanesecompanies

Sitagliptin: Merck
First in class in many countries

Troglitazone: Sankyo

SGLT-2 inhibitors(glucose reuptake inhibitors)
World-first concept in Japan

Vildagliptin: Novartis
Early DPP-4 concept
Canaglifozin (Mitsubishi Tanabe)
Domestically produced; world-first
concept
First in class in the United States

Tenegliptin: Mitsubishi Tanabe
DPP-4 inhibitor researched anddeveloped solely in Japan

Anagliptin: Research anddeveloped by Sanwa Kagaku;
Kowa involved from P3
onwards

Dapaglifozin (BMS/AZ)
First on European market 2012

Ipraglifozin (Kotobuki/Astellas)
First in domestic market
Manufactured by Kotobuki, jointly developed with
AstellasFig. 4.6 Chemical Structures of Representative Diabetes Drugs (2).

76

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

4.1.9.

Sodium Glucose Transporter-2 (SGLT-2)
Inhibitors
Amidst fierce competition over DPP-4 inhibitors, diabetes
drugs emerged with other new mechanisms of action. These
were the SGLT-2 inhibitors. Canaglifozin, the world’s first
SGLT-2 inhibitor, gained approval in the United States in
2013; this was a new drug that was Japanese in origin(Mitsubishi Tanabe Pharma). The drug was licensed to
Janssen Pharmaceuticals under the Johnson & Johnson
umbrella; approval was granted in the United States in March2013 and sales began immediately.
A polyphenol compound called phlorhizin started being
extracted from the bark of pear and apple trees in 1835. In
1966, it was reported that this compound had a renal
glycosuria inducing effect by means of a mechanism
preventing the reuptake of glucose by the kidneys (32).
However, the compound was long disregarded due to its
nephrotoxicity.
Some people, however, were interested in its
pharmacological effects. Kenji Tsujihara, a researcher at
Tanabe Seiyaku, considered the idea of treating a disease inwhich “glucose is present in the urine” (diabetes) with thereverse: a medication that “excreted glucose through theurine”. Of all the many different medications for diabetes,
this idea stands out as the most unique.
Although animal experiments using oral administrationachieved no results, administration by injection was found topromote urinary sugar excretion and thereby lower the blood
glucose level. A research project was commenced in 1990.
The reason for the lack of efficacy with oral administration
was that phlorhizin is a glycoside that bonds with glucose;when administered orally, it hydrolyzed into phloretin andglucose by the β-glucosidase in the digestive tract and lost its
medicinal efficacy. Tsujihara et al. at Tanabe Seiyaku used
this compound as a lead to identify the structure-activity
correlation; the first results were published in the Journal of
the Pharmaceutical Society of Japan in 1996 (33). Further
results were published the United States Journal of
Medicinal Chemistry after narrowing down the candidate
compound T-1095 (34). Later, cooperative partner Janssen
Pharmaceuticals began clinical trials in the United States in
2000.
However, these publications drew the attention of anumber of drug discovery companies, both in Japan andoverseas, who began their own research and development ofthese new diabetes drugs. Meanwhile, it was found during
clinical testing that the compound T-1095 broke down
considerably in the digestive tract, thereby requiring large
doses to be administered in order to produce any effect. Thisthrew up a red light for development, with the need for somekind of backup. With other companies catching up andproposing new mechanisms of action, Tanabe Seiyaku opted
to withdraw from the frontline of development. At this time,
Sumihiro Nomura, a medicinal chemist, drew on his priorknowledge and ingeniously came up with a backup within ashort space of time. The result was TA-7284 (Canagliflozin)(35). From late 2006 onwards, clinical testing was resumed
overseas by Janssen Pharmaceuticals and in Japan by Tanabe
Seiyaku.
Since then, clinical testing has been carried out on morethan 10,000 type 2 diabetics. Despite some physicians
expressing safety concerns for patients with poor renal
function, the drug was deemed to have good overall
tolerability and high efficacy; new first-in-class drug
approval was granted in the United States. According toanalysts, this drug is expected to achieve over $2 billion in
annual sales worldwide.
The kidneys contain tissue structures called glomeruli,
which filters the blood by means of the arterial bloodpressure, with the primary urine excreted through the renal
tubule. The renal tubule is divided into the proximal tubuleand the distal tubule. As the primary urine passes through,around 90% of the high concentration of glucose containedin it is reabsorbed by a protein transporter known as sodium
glucose co-transporter-2 (SGLT-2). The 10% of glucose
remaining in the proximal tubule is reabsorbed by SGLT-1,
meaning that 100% of the glucose is reabsorbed into theblood.
SGLT-1 is also expressed in the small intestine epithelial
cells outside of the glucose-transporting tubular epithelial
cells of the kidney. It plays a major role in glucose
absorption in the body. Selectively inhibiting SGLT-2 would
prevent the reabsorption of most of the glucose from therenal tubule, allowing it to be excreted as urinary sugar,
thereby lowering the blood glucose level. Further, SGLT-2
selectivity would mean there would be no hindrance to
SGLT-1 reuptake from the renal tubule, nor any hindrance tothe absorption of glucose from the alimentary canal, thus noexcessive hypoglycemia would be expected.
Despite concerns about infection of the urinary bladderand other areas of the urinary tract, clinical testing has shown
fewer side effects than expected. Currently, SGLT-2
inhibitors continue to be developed in Japan; as of 2014,
there are five types competing on the market.
These five SGLT-2 inhibitors include some of Japaneseorigin: Ipragliflozin, jointly researched and developed by
Kotobuki/Astellas, Tofogliflozin, manufactured by Chugai
Pharmaceutical, and Luceogliflozin, manufactured by Taisho
Pharmaceutical. Canagliflozin by Mitsubishi Tanabe Pharma
was released on the American market to become the world
first.
This gives a sense of strength of the research anddevelopment capabilities of Japanese drug discovery
companies.
4.1.10. Aldose Reductase Inhibitors
Epalrestat (Kinedak) is an aldose reductase (AR) inhibitor
developed by Ono Pharmaceutical. While glucose in the
body is mainly metabolized by glycolysis, the polyol
metabolic pathway was discovered in 1956, whereby aldose

Systematized Survey on the History of Drug Discovery with Technical Development

77

reductase reduces glucose to sorbitol, which is thenmetabolized into fructose by sorbitol dehydrogenase (SDH).
Although only a little glucose is metabolized by the polyol
metabolic pathway, under prolonged diabetic hyperglycemic
conditions, AR is activated and the amount of glucose
converted into sorbitol increases, thereby increasing theamount of sorbitol produced in the cells. In 1973, Gabbay et
al. empirically demonstrated that increased sorbitol plays aserious role in the onset of diabetic neuropathy and also
confirmed the presence of AR in the peripheral nerves, theretina, the crystalline lens and the kidneys; this study
identified elevated polyol metabolism as an onset mechanismof diabetic complications that had previously had no clearly
known cause.
Ono Pharmaceutical worked on researching anddeveloping AR inhibitors, focused on suppressing sorbitol
production. In 1992, the company obtained manufacturing
approval based on efficacy and results for “improving
subjective symptoms (numbness, pain) associated withdiabetic peripheral neuropathy, abnormal vibration
sensations and abnormal heart rate variability (where
glycosylated hemoglobin levels are elevated)”.
In 1998, six years after Epalrestat went to market, theMinistry of Health, Labour and Welfare issued a warning
about it due to 17 reported cases of impaired liver function inwhich a causal relationship could not be ruled out. A numberof other aldose reductase inhibitors being developed wereabandoned. There is as yet no definitive means forpreclinical testing to predict liver damage occurring
clinically.

Kenshū Gaidobukku (Training Guidebook for Diabetes
Specialists), 5th revision. Shindan to Chiryōsha 4(2012).
[2]

Harvey R. A., Maruyama K. & Yanagisawa T. (sup.
trans.): Illustrated Pharmacology, 5 Volumes.
Maruzen Publishing (2012).

[3]

Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini
M, Aldini G.: Advanced glycoxidation andlipoxidation end products: an overview of theirmechanisms of formation. Free Radical Research 47(12): 3-27 (2013).

[4]

Historiographical Institute The University of Tokyo(ed.): Dai Nihon Kokiroku (Old Diaries of Japan).
Shōyūki, Vol. 8, 40 & 43, Iwanami Shoten (2001); Vol.
4, 187, Iwanami Shoten (2001).

[5]

Wrenshall G., Hetenyi G. and Feasby W., Ninomiya R.
(trans.): Insulin Monogatari (Story of Insulin).
Iwanami Shoten (1965).

[6]

Reaven GM: Banting lecture: Role of insulin
resistance in human disease. Diabetes 37:1595607(1988).

[7]

Kaplan NM.: The deadly quartet: Upper-body obesity,
glucose intolerance, hypertriglyceridemia, andhypertension. Archives of Internal Medicine 149:
1514-1520 (1989).

[8]

Scott DA, Fisher AM: Studies on insulin withprotamine. Journal of Pharmacology and Experimental

Note 1: Source: Novo Nordisk website (2014).
Note 2: The United Kingdom Prospective Diabetes Study (UKPDS)

Therapeutics 58: 78-92 (1936).
[9]

Ozawa H., Murai Y. & Ozawa T.: Shinyaku 50-nen-shi

aimed to verify whether normalizing the blood glucose levels of type

(Tōnyōbyō Chiryōyaku) (50 Years of New Medicine

2 diabetes patients could suppress the onset/development in blood(treatment of diabetes)). The Japanese Journal for

vessel complications due to diabetes. Testing was carried out in 23
facilities around the United Kingdom, with multiple experiments
strictly controlling blood sugar levels and also examining thedifferences between medications.

History of Pharmacy 38 (1): 11-27 (2003).
[10] Kuzuya T. (ed.): Insurin, Bunshi Mekanizumu kara
Rinsho he (Insulin: From Molecular Mechanism toClinical Use). Kodansha Scientific Vol. 12. Kodansha

Note 3: A protocol is a written procedure outlining the plans andimplementation details for a clinical trial.
Note 4: According to the report from the 2nd Pharmaceutical Affairs
and Food Sanitation Council Subcommittee on Drug Safety in 2011,(1996).
[11] Maruyama K.: Shin Insulin Monogatari (Story of the
New Insulin). Tokyo Kagaku Dojin 166-168 (1992).
[12] Janbon M et al: Accidents hypoglycemiques graves par

the onset of bladder cancer was 14/2,605 (0.5%) in the Pioglitazone

un sulfamidothiodiazol. Montpellier Med. 441: 21-22

group and 6/2,633 (0.2%) in the placebo group. Excluding the onset(1942).

of bladder cancer within the first year of administration, the onset
rate was 6/2,605 (0.23%) in the Pioglitazone group and 3/2,633(0.11%) in the placebo group. Original reference: Lancet 366:1279,
2005.

rectifier subunit plus the Sulfonylurea receptor.
Science 270: 1166-1170 (1995).
[14] Iyakuhin Intabyū Fōmu (Drug interview form).

References[1][13] Inagaki N et al: Reconstruction of IKATP: An inward

The Japan Diabetes Society (ed.): Tōnyō-byō Senmoni

Euglucon. Chugai Pharmaceutical Co., Ltd. (2010).
[15] Kaku K.: Shinki Suruhoniruurea-zai Gurimepirido noKantō Sansei ni Oyobosu Eikyō (The Effect of Novel78

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchSulfonylurea Agent Glimepiride on Hepatic Glucose
Production). Journal of New Remedies and Clinics[27] Sankyō Hyakunenshi (100-year History of Sankyo).
Sankyo Co., Ltd. 365-369 (2000).

49:147-151 (2000).

[28] Lehmann JM, Moore LB, Smith-Oliver TA, Wilkinson[16] Seino Y. (ed.): Insurin Bunpitsu Sokushin-Yaku

WO, Willson TM, Kliewer SA.: An antidiabetic

SU-Yaku to Gurinido (Insulin Secretagogue SU Drugthiazolidinedione is a high aﬃnity ligand for

and Glinide). Fujimedical (2006).

peroxisome proliferator-activated receptor gammer.

[17] University Group Diabetes Program (UGDP): A study

Journal of Biological Chemistry 270: 12953-12956

of the eﬀects of hypoglycemic agents on vascular[29] Tontonoz P, Hu E, Spiegelman BM.: Stimulation ofMortality results. Diabetes 19: 785-830 (1970).

adipogenesis in fibroblasts by PPAR gamma2, a(1995)

complications in patients with adult-onset diabetes:[18] UK Prospective Diabetes Study (UKPDS) Group:

lipid-activated transcription factor. Cell 79:

Intensive blood-glucose control with sulfonylurea or
insulin compared with conventional treatment and risk

1147-1156 (1994).
[30] Steven E. Nissen, and Kathy Wolski: Effect ofof complications in patients with type 2 diabetes

Rosiglitazone on the Risk of Myocardial Infarction and(UKPDS 33). Lancet 352: 837-853 (1998).

Death from Cardiovascular Causes. The New England[19] The DECODE study group, glucose tolerance andJournal of Medicine 356 (24): 2457-2471 (2007).
[31] Takeda K. & Inagaki N.: Kan Beta-Saibō ni okeru

mortality: Comparison of WHO and American
Diabetes Association diagnosis criteria. Lancet 354:

GLP-1 Juyōtai wo kai suru c-AMP Seigyō Kikō no617-621 (1999).

Sūri Moderu-ka to Shimyurēshon Kenkyū (Numerical[20] Ikenoue T, et al.: British Journal of Pharmacology

modeling and simulation study of c-AMP control
mechanism via GLP-1 receptor in pancreatic β cells:

120: 137-145 (1997).
[21] Miller RA, Chu Q, Xie J, Foretz M, Viollet B,

Endocrinology / Diabetes / Metabolism Internal

Birnbaum MJ: Biguanides suppress hepatic glucagon

Medicine). Endocrinology, Diabetology & Metabolism

signaling by decreasing production of cyclic AMP.

35 (2): 141-148 (2012).

Nature 494 (7436): 256-60 (2013).

[32] McKee, F. W, Hawkins W. B.: Phlorhizin Glucosuria.

[22] Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy

Physiological Reviews 25: 255-280 (1945).

N, Depinho RA, Montminy M, Cantley LC: The[33] Tsujihara K, Hongu M, Saito K, et al.: Chemical andkinase LKB1 mediates glucosehomeostasis in liver andtherapeutic effects of metformin. Science 310:

Pharmaceutical Bulletin 44: 1174-1180 (1996).
[34] Tsujihara K., Hongu M., Saito K., Saito A. et al.:1642-1646 (2005).

Na+-Glucose Cotransporter (SGLT) Inhibitors as[23] Kobayashi H. & Furuyama N.: History of Innovative
Research and Drug Discovery at Takeda. Takeda

Antidiabetic Agents. 4. Journal of Medicinal Chemistry
42: 5311-5324 (1999).

Pharmaceutical Co., Ltd. 68-75 (Feb. 2011).

[35] Nomura S., Sakamoto S., Tsuda-Tsukimoto M. et al.:[24] Kameda Y, Asano N, Yoshikawa M, Matsui K.:

Discovery of Canagliflozin: A Novel C -Glucoside with

Valienamine as an α-glucosidase inhibitor. Journal of

Thiophene Ring, as Sodium-Dependent Glucose

Medical Chemistry 29: 1038-1046 (1987).

Cotransporter 2 Inhibitor for the Treatment of Type 2[25] Horii S, Fukase K, Matsuo T, Kameda K, Asano N,

Diabetes Mellitus. Journal of Medicinal Chemistry 53:

Masui Y.: Synthesis and α-d-glucosidase inhibitory6355-6360 (2010).

activity of N-substituted valiolamine derivatives aspotent oral antidiabetic agents. Journal of Medicinal

4.2 Medications for Hypertension

Chemistry 29: 1038-1046 (1987).
[26] Sugiyama Y. & Momose Y.: History of Innovative
Research and Drug Discovery at Takeda. Takeda
Pharmaceutical Co., Ltd. 92-99 (Feb. 2011).

According to the 2011 Patient Survey, conducted every
three years by the Ministry of Health, Labour and Welfare,
the total number of hypertension sufferers (patients assumed
to be receiving ongoing treatment) was 9.07 million (3.82

Systematized Survey on the History of Drug Discovery with Technical Development

79

million males and 5.26 million females). The number of

cerebral hemorrhage and ischemic heart disease since thepeople with undiagnosed hypertension is assumed to be

Second World War. Ca blockers, the ace ofseveral times higher. Although there are relatively few

anti-hypertensives, only started being administered for

subjective symptoms for hypertension, it is well known by

hypertension in the 1980s. Since then, however,most people today to cause stroke and heart disease.

anti-hypertensives have been well used clinically; according

The Japanese Society of Hypertension published thethe Pharma Japan Handbook 2010 published by Jiho,2014) in April 2014. While this revision maintained theanti-hypertensives amounted to ¥594 billion, while

diagnostic criteria for hypertension (criteria for commencing

vasodilators amounted to ¥328.4 billion. These figures were

hypertension medication treatment) at the existing values of

the highest sales figures of the medicinal categories.

“systolic blood pressure 140mm Hg or higher, diastolic

According to the website of the Ministry of Health,blood pressure 90mm Hg or higher”, the antihypertensive

Labour and Welfare, the average systolic blood pressure

target or non-binding target for lowering blood pressure forvalue reached its highest point in the mid-1960s, decreasing

young and middle-aged hypertension patients was relaxed

for both men and women after this peak. One reason for thisslightly from 130/85mm Hg to 140/90mm Hg to provide

decrease is the increase in the number of people receiving

uniform diagnostic criteria (office blood pressure). For

treatment for hypertensive diseases. In 1955, 61 in 100,000

elderly patients (75 years and over), the antihypertensive

people were receiving treatment for hypertensive diseases;

target was modified from 140/90mm Hg to 150/90mm Hg.

by 1975, this figure had risen to 475; by 2005, it was 513.

While it is true that these indicators are all biomarkers,

The mortality rates by leading causes of death mentioned

biomarker reference values are an important means ofat the beginning (from the Vital Statistics survey by the Vital,

diagnosis. These vary according to age and nationality,

Health and Social Statistics Office of the Minister’swhich may be confusing to the general public.

Secretariat of the Ministry of Health, Labour and Welfare)

Other than beta-blockers, which have been included todate, the four first-line drugs in the guidelines are
angiotensin II receptor blockers (ARBs), ACE inhibitors, Cashow the number of deaths from cerebrovascular diseases
start to rapidly decline from around 1970 onwards.
This suggests that the general population was increasing

blockers and diuretics (thiazides and thiazide analogs).

in awareness of hypertension and paying greater attention to

Beta-blockers “are recommended as first-line drugs for heart

diet and lifestyle, while anti-hypertensives prescribed by

failure, tachycardia, angina pectoris and myocardial

doctors also probably played a significant role.

infarction”.
When hypertension is prolonged

Tracing the history of hypertension research, clinicians: (i) Arteriosclerosis

appear to have treated hypertension objectively since theprogresses, leading to thickening of the vascular wall andinvention of the sphygmomanometer by Scipione Riva-Rocci

narrowing of the vascular cavity,of Italy in 1896. Studies on blood pressure regulation by thewhich results in greater

susceptibility to cerebral hemorrhage due to cerebrovascular

central nervous system began in the early 20th century; indamage or stroke due to vascular stenosis or occlusion. The

1936, Astley Cooper found that the blood pressure in a dog

statistics for 2009 indicate that there were 130,000 deaths

could be elevated by ligation of the common carotid artery.

from cerebrovascular diseases and 84,000 deaths fromAt the time, hypertension was not known as a risk factor.

myocardial infarction and ischemic heart disease. Infarction

In 1954, soon after the appearance of anti-hypertensives, A.

and hemorrhage accounted for 60% and 40% respectively.

M. Fishberg published the opinion that “it is better not to

Subarachnoid hemorrhage is also a serious disease caused by

notify hypertensive patients of their blood pressure reading if

hypertension. (ii) The pumping action of the heart is elevatedthey have no symptoms” (Fishberg A. M.: Hypertension anddue to hypertension, resulting in cardiac hypertrophy if

Nephritis, 5th ed. Lea & Fibiger, 1954 (1)).

prolonged. If this happens, there is a relative decrease in

According to Kōketsuatsu no Igaku (2), “in 1944, U.S.

myocardial blood flow, along with thickening of the

President Franklin Roosevelt undertook a strict reduced-salt,

coronary artery and smaller arteries, increasing susceptibility

weight loss diet to combat his hypertension. Having visited

to myocardial infarction and angina pectoris. (iii) If diabetes,

him, British Prime Minister Winston Churchill commented

high cholesterol, obesity and other hypertension risk factorsthat the President appeared not to eat any meals and looked

become more serious, the incidence rate for ischemic heart

haggard, thin, aged and lacking vitality. In spite of this strict

disease becomes extremely high. These are well-known facts

lifestyle improvement, there were no effective

today.

anti-hypertensives in those days and the President passed

However, the lifestyle disease hypertension has had a very
short history, only becoming known as a risk factor for80

to the 2007 production values by medicinal category listed in

Guidelines for the Management of Hypertension 2014 (JSHaway from a cerebral hemorrhage in the spring of 1945”.
This story highlights the importance of anti-hypertensives

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

(Note 1).
The U.S. government started academic epidemiologicalsurveys on heart diseases in 1948. That same year, alarge-scale prospective cohort study was undertaken with thecooperation of the residents of Framingham, Massachusetts,
as a countermeasure against rising incidences ofcardiovascular complications (Note 2). This was thewell-known Framingham Heart Study (see Section 4.3.
Medications for Hyperlipidemia). This study recorded bloodpressure as a risk factor in the report for the 1960s and 1970s(4:14).
Hypertension falls into two categories: “secondary
hypertension”, which has a clear cause and accounts foraround 10% of patients, and “essential hypertension”, which
has no identifiable cause and accounts for the majority ofpatients. However, studies seeking the cause of essential
hypertension have found various direct causes that raise or
lower the blood pressure.
Blood pressure refers to the pressure applied to thevascular wall and is represented by “cardiac output” ×“peripheral vascular resistance”. Cardiac output is the heart
rate multiplied by the blood volume pumped out by one
contraction of the heart; peripheral vascular resistance is
proportional to the hardness of the blood vessel and inversely
proportional to the cross sectional area of the blood vessel.
Theoretically, reducing these factors would be enough tolower the blood pressure. Early efforts focused on
medications to reduce the heart rate and diuretics to lower
the blood volume, thereby regulating the cardiac output or
reducing the blood volume (see Fig. 4.2.1).
While increased peripheral vascular resistance is mainly
due to arteriole vasoconstriction, progress was made on
developing specific antagonists targeting the receptors forcentrally or peripherally acting sympathomimetic substances
as a constricting factor.
In 1949, Euf von Euler identified noradrenaline as aneurotransmitter for sympathetic nerve activity andestablished the relationship between the sympathetic nerves
and hypertension. Reserpine, empirically known to have ahypotensive effect, was found to cause this effect byinhibiting the reuptake of neurotransmitter into theneurotransmitter storage granules in the sympathetic nerve
endings (synapses), thereby causing catecholamine depletion.
In 1953, Reserpine was approved by the FDA and was
widely prescribed in the 1960s and 1970s.
During this time, the idea of blocking the sympathetic
nerves was devised as a means of lowering blood pressure,although it is not used today. Sympatholytic agents (such as
guanethidine, alpha-methyldopa and clonidine) andganglionic blockers (such as hexamethonium) weredeveloped. Later, substances causing blood pressure
elevation were successively identified, including adrenaline,
noradrenaline and angiotensin. Various types of drugs began
to be developed to deal with each of these.
In 1967, a large-scale clinical intervention trial (Note 3) was
conducted by the Veterans Administration Study (VA) and it
was reported for the first time that anti-hypertensive
treatment suppressed cardiovascular complications (3). The
trial used a comparative study against a placebo group; thedrug administration group was given a combination of threeof the more potent anti-hypertensives available at the time
(hydrochlorothiazide + reserpine + hydralazine).
After that, clinical trials mainly involved diuretics. A 1977
study by the United States Public Health Service (USPHS)
indicated that while anti-hypertensive treatment did notprevent serious cardiovascular events in mild hypertension
cases, it did prevent the condition from deteriorating.
Successive intervention trial results were reported, such as
the Australian National Blood Pressure Study (ANBPS)(1980) and the Oslo Study (1980), but these results revealed
that although anti-hypertensives significantly suppressed theonset of cerebral hemorrhage, they were ineffective against
the onset of ischemic heart disease. Later, beta-blockers weredeveloped and results were reported to indicate a secondary
prevention of myocardial infarction, demonstrating theirefficacy as an anti-hypertensive. Several comparative studies
were conducted comparing beta-blockers and diuretics.
Although beta-blockers were found to be effective at theendpoint of heart disease onset, there was no difference inother indicators (4:124-128).
Based on the results of basic research from these clinical
trials, efforts continued in drug discovery to reduce thecauses of hypertension. Research and development wasundertaken on diuretics to reduce body fluids, beta-blockers
to lower the heart rate and alpha-blockers and calcium
channel blockers to reduce the peripheral artery resistance.
The focus fell on renin, secreted from the kidneys, and therelated angiotensin; developments included angiotensin II
converting enzyme inhibitors (ACE inhibitors) andangiotensin II inhibitors. With the development of drugs withseveral different mechanisms of action, anti-hypertensives
became a highly satisfying field of medicine.
The importance of renal blood pressure has recently beenrealized; it is now known that there are a number of different
factors that directly cause elevations in blood pressure.
Anti-hypertensives are administered to patients inaccordance with their pathology, with consideration given to
the relevance of each factor for that patient. However, even
now there is still no established theory as to the cause of
essential hypertension, which is dominant further upstream
than these direct causes of elevations in blood pressure.
Figure 4.7 shows the points of action of anti-hypertensives.
AT inhibitor

Blood pressure = cardiac output (pulse rate × blood volume) ×
peripheral vascular resistanceSympathetic nerve
stimulation

Diuretic

Beta-blocker

Increased Na in the body

Increased body fluids to maintain osmotic pressure

Alpha-blocker
Calciumchannel blocker

Increased pulse

Increased blood
volumeIncreased arteriole resistance
Increased cardiac output

AT inhibitor
ACE inhibitor
Angiotensinogen

Elevated bloodpressure

Source: Umezu 2014

The symbols
andrepresent the receptors that cause hypertension and their agonists.
Agonists include α, β, AT (angiotensin II), etc.
Items surrounded by white squares represent anti-hypertensives and their respective points of action.

Systematized Survey on the History of Drug Discovery with Technical Development

81century, when sulfa drugs were found to have a diuretic
effect. This was later found to be due to the inhibition ofcarbonic anhydrase and analogs began to be synthesized.
During this time, from around 1957, thiazide diuretics, loop
diuretics and potassium-sparing diuretics were developed.
Although these three types of diuretics all act bypromoting the excretion of Na+ and water in the uriniferous
tubules, they differ in their point of action. Figure 4.8 shows
the points of action of different diuretics.
Thiazide diuretics mainly produce a diuretic effect byinhibiting the reuptake of Na+ and Cl- in the distal tubules.
Hydrochlorothiazide and trichlormethiazide were used for
this; however, these have moderate potency as diuretics dueto their poor diuretic action. Nevertheless, since these arecheap and perform adequately as anti-hypertensives, they arestill recommended by the American Hypertension Guidelines(JNC7).
Loop diuretics such as furosemide act at the ascending
limb of the loop of Henle in the kidney (Note 4). While they do
not have a strong hypertensive effect, they do have a strong
diuretic effect, which prevents the exacerbation of renal
function deterioration; accordingly, they are effective in

Although diuretics have long been recognized as mild
anti-hypertensives, some side effects have also been
identified, such as elevated blood glucose and uric acidlevels. However, these elevated blood glucose and uric acidlevels have been found to be the result of excessive fluid
excretion due to overly high dosages of diuretics; low-dosage
diuretic usage has now become standard practice.
In the 1980s, alpha-blockers, ACE inhibitors and calcium
channel blockers were developed as a means of reliably
lowering blood pressure. While these anti-hypertensives
were initially administered concomitantly with diuretics, they
have none of the metabolic side effects (hypokalemia,
hyperuricemia, hyperlipidemia, glucose intolerance) usuallyassociated with diuretics. Patients in Japan have long awaited
drugs that were less complicated to use than diuretics and are
advocating individualized treatment rather than
one-size-fits-all treatment protocols.
Various anti-hypertensives are now being developed withfewer side effects. Clinics are entering an era in which
different options are available according to patient pathology.
Diuretics are being re-evaluated, although few are being usedas standalone treatments due to high incidences ofhypokalemia and renal dysfunction.

improving edema and hypertension accompanying renal
dysfunction. These drugs increase susceptibility to

and water in the uriniferous tubules by antagonizing
aldosterone (a hormone known as a mineral steroid) in thealdosterone-dependent Na+/K+ exchange sites in the distal
tubules and collecting tubules. Since they inhibit K+

Thiazide diuretics

Glomeruli
Aldosterone
antagonists
Distal tubules

hypokalemia and hyperuricemia.
Potassium-sparing diuretics promote the excretion of Na+

Aldosterone antagonists are also classed as
potassium-sparing diuretics. While the point of action ofdiuretics is the inhibition of Na+ and K+ reuptake, thetransfer of ionic species differs according to thetransporter or enzyme acted on.

Potassium-sparing
diuretics

excretion, they are characterized by no K+ loss. These drugs
include spironolactone and eplerenone. Spironolactone is acompound developed in 1957 by Kagawa et al. of Americancompany G. D. Searle as a result of systematic exploratory
research on aldosterone antagonists (23). Eplerenone wasdeveloped by Pharmacia (now Pfizer) and selectively inhibits
the binding of aldosterone to the mineralocorticoid receptors.
Recent research has shown that aldosterone is produced in
the heart and vascular cells, as well as the adrenal cortex.
Reports also indicate that the mineralocorticoid receptors on
which aldosterone acts are found in various sites throughout
the body, such as the heart and vascular wall, not just in thekidneys. The importance of aldosterone in cardiovasculardiseases has begun to be recognized and there are great
expectations for the protective effects of aldosterone
antagonists on the internal organs. Clinical trials foreplerenone began in 1997; it was adapted for hypertension in2007.
Triamterene produces a potassium-sparing diuretic effect82

Carbonatedehydrataseinhibitors

Capillaries

4.2.1.
Diuretics
The history of diuretics can be traced back to the early 20thby inhibiting amiloride-sensitive Na+ channels; it cansometimes induce hyperkalemia.

Proximal tubules

Fig. 4.7 Points of Action of Anti-Hypertensives.

Loop diuretics

To thecollecting
tubules

Loop of Henle

Fig. 4.8 Points of Action of Diuretics
4.2.2.
Alpha-Blockers and Beta-Blockers
Adrenergic receptors include α-receptors and β-receptors;
the β-receptors include β1-receptors, which are mainlypresent in the myocardium, and β2-receptors, which arepresent in the bronchial smooth muscle. Blocking the
β1-receptors (i) reduces myocardial contractility, (ii) lowers
cardiac output, (iii) inhibits atrioventricular conduction and(iv) reduces renin secretion by the adrenal glands, resulting
in a hypotensive effect. However, since β-blockers with noβ1 selectivity block other β-receptors throughout the body,they are more prone to producing various side effects.
Specifically blocking the β2-receptors can cause bronchial

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchfew second-generation products were produced (Note 5).

constriction and therefore must be avoided in asthmaticpatients.

By contrast, α1-blockers acted on the arteriole smooth

However, β-receptors are also present in the sympathetic

muscle receptors to inhibit smooth muscle contraction,

nerves (presynaptic cells); the stimulation of those receptors

thereby lowering the peripheral vascular resistance andhas been found to be a noradrenaline-releasing mechanism.

consequently lowering the blood pressure. With α-receptors

Non-selective β-blockers are presumed to have a hypotensive

widely distributed throughout the body, there are manyeffect by inhibiting sympathetic nerve activity. Beta-blockers

α-receptor subtypes. While α1-receptors are found in smoothwith partial agonist activity have also emerged, making formuscle cells, α2-receptors are also found in presynaptic cells

even more complex analysis of their pharmacological effects.

and inhibit the release of catecholamine. Inhibiting these

The β-blocker propranolol (Zeneca; now AstraZeneca) hit

receptors promotes the release of catecholamine, which

the Japanese market in 1966, indicated for arrhythmia andcauses side effects. Accordingly, selective α1-blockers are

angina pectoris; in 1978, it was adapted as anpreferable. First-generation selective α1-blockers includeanti-hypertensive. The first anti-hypertensive to be approved

prazosin (1981, Pfizer) and bunazosin (1985, Eisai), used on

in Japan as the β-blocker was pindolol (Ciba-Geigy; now

patients with hyperlipidemia and abnormal glucose tolerance

Novartis), launched in 1973. Many Japanese pharmaceutical

for their carbohydrate and lipid metabolism improving

companies were involved in the development of β-blockers;

effects. These gradually fell out of use due to side effects

bufetolol (Yoshitomi Pharmaceutical) was the firstsuch as orthostatic hypotension.

domestically-produced β-blocker to emerge on the market in

Drugs developed to block both α- and β-receptors include

1974. However, it was not adapted as an anti-hypertensive.

amosulalol (1988, Ono /Dainippon), arotinolol (1985,

Other drugs emerged in succession, including indenolol in

Sumitomo) and carvedilol (Boehringer Ingelheim).

1980 by Yamanouchi Pharmaceutical, carteolol in 1981 by

Arotinolol has a potent β-blocker effect that is eight times

Ostuka Pharmaceutical and nipradilol in 1988 by Kowa.

more powerful than its α-blocker effect; designed to suppress

These are the first-generation β-blockers.

peripheral vascular resistance, this was a proprietary new

AstraZeneca then synthesized a drug with greater β1

anti-hypertensive drug development by Sumitomo

selectivity in order to reduce side effects; this was jointly

Pharmaceuticals directly following the establishment of thedeveloped with Novartis. The once-a-day medicationcompany.

metoprolol was launched on the Japanese market in 1983.

Fig. 4.9 shows the chemical structures of some
representative diuretics and β-blockers.

AstraZeneca also released atenolol in 1983, a once-a-day
β-blocker with greater selectivity. Metoprolol wassuperseded by atenolol internally within AstraZeneca.

Diuretics

Beta-blockers

Nadolol (discovered by Squibb in 1970 and developed by

Propranolol: the first
β-blocker Zeneca

Dainippon Pharmaceuticals) was launched in 1986 with

Furosemide: loop diuretic
Aventisgreater compliance as a once-a-day medication, although it
was non-selective. In 1990, Tanabe Seiyaku licensed

Atenolol: second-generation
AstraZeneca

bisoprolol from E. Merck and was granted approval thatsame year. Although this was the 20th β-blocker on the

Hydrochlorothiazide: thiazide
diuretic Merck/Banyu

Japanese market, it achieved a top ranking in sales.

Arotinolol: α/β blocker
Sumitomo Pharmaceuticals

Although β-blockers were also effective for ischemic heartdisease and arrhythmia because they lowered the cardiac
output to reduce the workload on the heart, they were known

Spironolactone: potassium-sparing diuretic
Pfizer

as “delicate balance” medications that had to be increased

Prazosin: α-blocker

Pfizergradually; they were problematic to use, as excessive dosage
could increase the burden on the heart and cause various

Fig. 4.9 Chemical Structures of Representative

cardiac disorders. Beta-blocker sales began to decline withDiuretics and Beta-Blockers

the eventual emergence of calcium channel blockers and
ACE inhibitors.

4.2.3.

Analogs would have been simple to synthesize using theCalcium Channel Blockers

The history of calcium channel blockers began with theβ-blocker structure and many companies in Japan announced

discovery that the cardiac suppression effect of thetheir candidacy for the first-generation drugs. However, very

newly-developed coronary vasodilator verapamil, unlike

Systematized Survey on the History of Drug Discovery with Technical Development

83nitroglycerin, suppressed myocardial contraction. While it
was reported that atrial cell depolarization was caused byearly Na+ influx and late Ca2+ influx, the mechanism ofaction of verapamil was found to be due to the blocking of
Ca2+ influx.
The idea of calcium channel blockers was proposed in1972 by Albrecht Fleckenstein of Germany (5), but it gained
few supporters, as the main remedies for angina pectoris in
Europe at the time were dipyridamole and β-blockers.
Further, in 1972, Mototaka Murakami of Kanazawa
University reported on the anti-hypertensive effects ofnifedipine (6).
The Japanese drug diltiazem was the first to substantiate
this idea of calcium channel blockers. Diltiazem was released
to market in 1974 by Tanabe Seiyaku as an “anti-anginal
having a mechanism of action due to blocking Ca2+ influxand having a myocardial contraction suppressing effect and apulse-regulating effect”. It later came to be used in 110
countries around the world, with sales peaking at over $100
billion.
According to Tanabe Seiyaku’s company history,companies in the West started taking an interest in diltiazem
from around 1976 due to its unique mechanism of action.
After several international symposia, Japan deemed it to besafe and highly effective. When it was launched in the
United States in 1982, it was received as a “life-saving
medicine”. While diltiazem was originally used for its
effectiveness against stable angina by suppressing thickblood vessel spasms, once it was found that exercise-induced
angina involves coronary blood vessel spasms, the drug was
adapted to be effective against exercise-induced angina as
well. In 1982, it was adapted again for hypertension. Thiswas possible due to the fact that its vasodilatory action by
inhibiting the influx of calcium to the vascular smoothmuscle cells results in a hypotensive effect (7, 8).
However, the results of a clinical trial found that “theadministration of diltiazem to myocardial infarction patients
showed no difference in incidence rate from the
non-administered group”, thus casting doubt on its
effectiveness on angina pectoris and myocardial infarction (9).
It was pointed out that although this short-acting drug causes
rapid vasodilation, the effect quickly diminishes, which
could potentially disrupt the blood pressure due tovasoconstriction. In response, a controlled-releaseformulation of diltiazem, taken once or twice daily, wasdeveloped, thereby improving its effectiveness against
angina pectoris and also improving its anti-hypertensive
effect. While intense development competition later ensued
for calcium channel blockers, the original Japanese diltiazem
was a great success as one of the compounds that laid thefoundation for clinical utility as an anti-hypertensive with acalcium channel blocking effect.
There are three types of calcium channel blockers withthree basic structures: phenylalkylamines (such as verapamil),benzothiazepines (such as diltazem) and dihydropyridines(such as nifedipine). As these grew more highly regarded as
effective first-generation calcium channel blockers, issues
were raised with side effects and excessive dosage frequency
and volume due to shorter half-lives. Demand grew for drugs

84with milder action and fewer side effects, leading to theemergence of a succession of second-generation drugs that
required less frequent dosages. However, recent policies
have focused on extending the dosage duration throughinnovations in dosage form; some attention has even been
given to reassessing first-generation calcium channel
blockers.
The emerging second-generation drugs included
nilvadipine (1989, Fujisawa Pharmaceutical), taken twice
daily, and nisoldipine (1990, Bayer), manidipine (1990,
Takeda Pharmaceutical), benidipine (1991, Kyowa Hakko
with collaborative research by Nagoya City University
Faculty of Pharmaceutical Sciences) and barnidipine (1992,
Yamanouchi Pharmaceutical), each taken once daily. In
addition to these, other domestically-produced drugs werealso released on the market, including efonidipine (1994,
discovered by Nissan Chemical and jointly researched by
Zeria Pharmaceutical), cilnidpine (1995,
Fujirebio/Ajinomoto) and aranidipine (1996, Maruko/Taiho).
Nitrendipine (Bayer) also emerged in 1998. Thus, theanti-hypertensive market in Japan bloomed to life with asuccession of calcium channel blockers following on fromthe β-blockers.
While these drugs had favorable anti-hypertensive effects,
as with nifedipine, there were still a number of drawbacks
with side effects as the dosage amount increased, including
facial flushing, heart palpitations and headaches, resulting
from tension on the reflex sympathetic nerves due to rapid
decrease in blood pressure. Later, calcium channel blockers
were developed that had greater sustained efficacy and fewerside effects. One such drug was amlodipine (1993, Pfizer),
which had a half-life of 36 hours, a far greater duration ofaction than any of the second-generation drugs. These were
the third-generation calcium channel blockers and included
azelnidipine (2003, Ube/Sankyo).
There are now dozens of calcium channel blockers incurrent use and it is possible to select the most appropriate
one for the pathology, although these cannot be used on
patients with acute myocardial infarction, diabetic
nephropathy, congestive heart failure or similar (10, 11).

Papers have been published questioning the safety ofcalcium channel blockers since 1995 as the “calcium channel
blocker controversy” has unfolded. A report by Pahor et al.
on a series of case-control studies identified the possibility
that calcium channel blockers increase the risk of cancer (12).
However, these reports have come under repeated criticism
for the testing methods and scale used, as well as the fact thatthe medication history was unclear; the need for longer-term
prospective studies has been pointed out.
Meanwhile, the Syst-Eur trial (13) and the STONE study(14)
have confirmed that calcium channel blockers do notincrease the risk of cancer. A report on the relative risk ofcancer in patients administered with β-blockers (14) also
stated that calcium channel blockers do not increase the riskof cancer, while a report (16) by the Ad Hoc Subcommittee ofthe Liaison Committee of the WHO/ISH (Note 6) and the US
hypertension guidelines JNC-VI (Note 7) also take a negative
opinion regarding the cancer risk of calcium channel
blockers.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

4.2.4.

Renin/Angiotensin Blockers

ACE Inhibitors

In 1898, Swedish medical scientists Robert Tigerstedt and

The first ACE inhibitor, captopril (1983, Sankyo/Squibb),

Per Bergman noted that administering animals with an

was put to the test through widespread clinical use. Various

extract from the kidneys of other animals caused a bloodissues began to be reported, including the rapid manifestationpressure elevation reaction; they named this substanceof its hypotensive effect, the need to administer it three times“renin”, with the idea that it came from the kidneys. In 1934,a day due to the short duration of its hypotensive effect andAmerican medical scientist Harry Goldblatt used animal

the relatively high incidence rate of side effects, including

experiments to test the question proposed by Richard Brightrashes, distorted sense of taste and dry coughing. In 1988, theon whether renal glomerular arteriosclerosis precedes

first domestically-produced ACE inhibitor hit the market in

hypertension or if arteriosclerosis progresses after

the form of alacepril (Dainippon Pharmaceuticals), with ahypertension. Goldblatt concluded that hypertension is not

reduced dosage frequency. This was a captopril prodrug andcaused by arteriolar stenosis, but by a hormone-likestill contained an SH-group.

substance released by the kidney following stenosis. He also

The second-generation drug enalapril (1986,

stated that the causative substance was renin, as mentioned

Banyu/Merck) had the SH-group present in captopril

by Tigerstedt (2:76-85).

substituted for a COOH-group to alleviate the side effects.

Research on renin continued, with the renin-angiotensin

Substituting the SH-group suppressed the rashes and the dry

system found to be one of the mechanisms that control blood

coughing. Various companies in Japan rapidly embarked onpressure. Renin (a protease) secreted by the kidneys acts on

new developments to overcome these issues; later,

the angiotensinogen in the blood to produce angiotensin I.

fully-Japanese “non SH-group” ACE inhibitors hit theThis peptide was found to convert into angiotensin II throughmarket. In 1989, delapril (Takeda Pharmaceutical) was

the action of an enzyme known as angiotensin-converting

launched, with a slow and sustained hypotensive effect. In

enzyme (ACE); angiotensin II was found to be one of the1990, Eisai released cilazapril, licensed from Roche Products

most powerful substances in the body for vasoconstriction.

(UK), which only need to be administered once a day. In

Angiotensin III and IV also exist, but their effects are not as

1993, imidapril (Tanabe Seiyaku) was launched as an

potent as angiotensin II. Angiotensin II constricts the bloodanti-hypertensive; in 2002 it was approved for treatment ofvessels by binding with the angiotensin II receptors (AT1) indiabetic nephropathy accompanying type 1 diabetes. In 1994,

the arteriolar smooth muscle; in the heart, this increases the

Sankyo launched temocapril as an anti-hypertensive.

cardiac output, producing hypertensive conditions. It is also

Temocapril was also biliary and renally excreted and could

known to have the effect of increasing the glomerular

accordingly be used as a once-a-day prodrug for patientsfiltration rate by selectively constricting the efferent

with renal dysfunction.

arterioles of the renal glomeruli and promoting the secretion

While angiotensin I converts into the vasopressorof aldosterone from the adrenal cortex by binding to thesubstance angiotensin II by means of ACE, angiotensin II is

receptors in the adrenal cortex. This aldosterone activity

also produced by chymase secreted by mastocytes (Fig.

promotes the reuptake of sodium by the collecting tubules in4.10).

the kidneys, causing a vasopressor effect from an increase inbody fluids. Assuming that the renin-angiotensin system

Angiotensinogenplays a significant role in regulating the blood pressure, withhypersecretion of renin causing hypertension, the hypothesis
has emerged that interrupting part of this process should

Kallikrein

Angiotensin I

Bradykinin

Substance P

ACE/kininase II

Chymaselower the blood pressure (17, 18).

Kininogen
Renin

Angiotensin II

Angiotensin Converting
EnzymeDegradation product peptide

To that end, drug discovery research began to focus on (i)preventing the production of angiotensin II by inhibiting
Receptor (AT1)

ACE, (ii) using angiotensin II receptor AT1 antagonists toinhibit signal transduction and (iii) inhibiting renin activity.
As expected, clinical studies found drugs based on (i) and (ii)to have definite hypotensive effects.

Angiotensinogen converts to angiotensin I by enzyme (renin) action.
It converts to angiotensin II by further enzyme (ACE) action.
ACE also has kininase II activity and also breaks down bradykinin and substance P.
ACE inhibition is thought to cause dry coughing by increasing substance P.

Fig. 4.10 Renin-Angiotensin System andKinin-Kallikrein System

Systematized Survey on the History of Drug Discovery with Technical Development

85

potential issues, making it possible for such a drug to be used

ACE has two enzyme activities; it acts as kininase II to
break down and metabolize bradykinin and substance P.

on patients who experienced side effects from ACE

Even in this route ACE (kininase II) acts in a way that

inhibitors. Accordingly, drug discovery companies all beganelevates blood pressure by breaking down bradykinin, which

to explore this field as well. There were two known types of

has a blood pressure lowering effect and an algesic effect.

angiotensin receptors: type I and type II; these

However, the use of ACE inhibitors presumably means not

anti-hypertensives targeted the type II receptor AT1.
In 1998, losartan (Merck) was released on the Japanese

only suppressed production of angiotensin II, but also
overproduction of substance P (which acts on the nerves

market. Takeda Pharmaceutical launched candesartan the

responsible for coughing and swallowing during normal

following year. The 4-8mg daily dosage for candesartan waseating and drinking), as it does not break down properly, as

far lower than the 25-50mg daily dosage for losartan and thewell as other side effects, including dry coughing and other40-80mg daily dosage for valsartan, released the following

various effects of non-angiotensin bradykinin systems(8, 9).

Fig. 4.11 shows the chemical structures of representative
calcium channel blocker and ACE inhibitor compounds.

year. Valsartan had been synthesized by Swiss company
Novartis Pharma in 1989, but was launched in Japan in 2000
by Ciba-Geigy Japan (now Novartis Pharma). These early
first-generation drugs delivered a superior hypotensive effect

ACE inhibitors

as anticipated, while also avoiding the side effects of dry
coughing and angioedema that had plagued the ACE
inhibitors. Later, the second generation of value-added ARBs

Captopril: Squibb/Sankyo
The first domestic ACE inhibitor

Delapril: Takeda Pharmaceutical
Third-generation domestically-produced
ACE inhibitor

Calcium channel
blockers

hit the market. Nippon Boehringer Ingelheim launchedtelmisartan in 2002, while irbesartan, jointly developed by
Shionogi and Dainippon Pharmaceuticals, was launched in2008. These ARBs were marketed as being suitable fordiabetes and heart failure as well. They were reported ashaving a powerful PPARγ bonding effect and an
insulin-resistance improving effect, similar to

Nifedipine: BayerFirst-generation calcium channel
blocker

Benidipine: Kyowa Hakko
Sustained second-generation, domestically
producedthiazolidine-analog diabetes drugs (see Section 4.1.6.
Thiazolidine Derivatives). They bond with thiazolidine
transcription factor PPARγ to suppress the production ofseveral proteins that set the stage for insulin resistance andhave accordingly been used as diabetes drugs, while showing

Azelnidipine: Ube Industries
Third-generation, domestically
produced

Amlodipine: Pfizer
Widely used worldwide

Diltiazem: Tanabe Seiyaku
Proposed the concept of calcium channel
blockers

promise for using this effect combined with other effects.
Basic research has also shown them to bond with PPARα,although fibrates also have this mechanism of action; thisinhibits the growth of triglycerides. (See 4.3.3.
Hyperlipidemia – Fibrate Lipid-Lowering Drugs.)
The discovery of drugs with a new effect among thesecond-generation AT1-blocking ARB anti-hypertensives isalso very interesting from the perspective of the causes ofmetabolic syndrome, combining hypertension,
hyperlipidemia and diabetes.

Fig. 4.11 Chemical Structures of Representative
Calcium Channel Blockers and ACE Inhibitors
Angiotensin II Receptor Blockers (ARBs)
Research began on angiotensin II receptor blockers with
the idea of overcoming the shortcomings of ACE inhibitors.
It was already known that angiotensin would be synthesizedby other enzymes even if ACE were completely suppressed.

Sankyo launched olmesartan in 2004, with a powerful
AT1 receptor bond. Azilsartan, known as a super ARB, wasreleased by Takeda Pharmaceutical in 2012.
Besides inhibiting ACE, these ARBs have also beenreported to have a direct protective effect on the kidneys by
expanding the efferent arterioles of the kidneys, thereby
lowering the pressure in the glomeruli. Fig. 4.12 shows thechemical structures of representative ARBs.

It was also predicted that side effects would be caused if
ACE inhibitors activated the bradykinin systems, but directly
blocking the angiotensin II receptors would eliminate these86

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchcombination of ARB and HTC.
Synergizing anti-hypertensives with different mechanismsof action made it possible to not only reduce the amount ofingredients used and increase the efficacy of the drug, butalso to reduce the side effects as well. This also led toextended life expectancy for basic drugs, which became a
new strategy for drug discovery companies.
Combination drugs made up of anti-hypertensives andstatins (lipid-lowering agents) began to emerge, as did
combination drugs made up of multiple diabetes drugs withdifferent mechanisms of action. Further attention will begiven to combination drugs for lifestyle-related diseases in
the future.

ARBs

Candesartan: Takeda PharmaceuticalFirst-generation domestically-produced
ARB

Losartan: Merck
The first domestic ARB

Azilsartan: Takeda Pharmaceutical
Second generation, domestically
produced

Olmesartan: Daiichi
SankyoSecond generation,
domestically produced

Fig. 4.12 Chemical Structures of Representative ARBs
Renin Inhibitors
In 2009, nearly two decades after the first ARB, losartan,
was approved, Japan gave the approval for aliskiren, a newrenin-angiotensin system anti-hypertensive. It was adapted
for hypertension and demonstrated a hypotensive effect whentaken once daily. It was produced by Ciba-Geigy (nowNovartis Pharma) and marketed widely around the world. Asa renin inhibitor, aliskiren acted farther upstream than ACE
inhibitors and ARBs to suppress the production ofangiotensin I; accordingly it was not accompanied by theincrease in angiotensin II as found with the use of ARBs.
Further, since it suppressed the production of angiotensin I, it
was expected to also reduce the amount of “angiotensin II
synthesized by non-ACE enzymes, which ACE inhibitors
were not able to suppress” (Note 8).
It was also thought not to incur dry coughing and otherside effects, since it did not inhibit the breakdown ofbradykinin as the ACE inhibitors did (23).
4.2.5.
Anti-Hypertensives and Combination Drugs
While drug combinations were found in Chinese medicine
and cold remedies, government regulation was placed onprescription drugs in the 1990s, meaning that combination
drugs were expressly not approved for patients with chronic
lifestyle-related diseases. Where a patient needed to take two
or more drugs with similar efficacy for a disease, they had totake multiple single drugs together. However, it was foundthat greater compliance was achieved when patients took
combination drugs than multiple single drugs; with many
combination drugs being used overseas in the 21st century,
they began to draw attention in Japan as well. As a result, theMinistry of Health, Labour and Welfare issued aderegulation notice in 2005.
Many anti-hypertensives in particular used several
different drugs in combination. Approval was given for
combination drugs made up of the highest-selling single-drug
ARBs and diuretics (hydrochlorothiazide HCT andtrichlormethiazide TCM), as well as ARBs and calcium
channel blockers. In 2006, MSD released Preminent®, a

4.2.6.
Hypertension Guidelines
Although the medicinal efficacy of anti-hypertensive
drugs is evaluated by clinical study (clinical trial) before
application is made for approval, after a drug goes to market,
many large-scale clinical trials are conducted over long
periods of time on large numbers of patients in order tocarefully examine the efficacy (indicated diseases,
concomitant drugs, dosage) and the side effects. The clinical
trials essentially look for: (i) whether the mortality rate
decreases; (ii) whether the incidence rate of the main disease
decreases; (iii) whether the side effects decrease; (iv)whether the quality of life (QOL) improves. The criteria on
which these are determined are called true endpoints.
However, since in reality it is difficult to determine the actual
mortality rate or disease onset within a short space of time,surrogate endpoints that can be assessed in the short term areused instead. While the surrogate endpoints make it possible
to gather a lot of data, in many cases they do not represent
the true medicinal efficacy. Many clinical studies have been
undertaken using these surrogate endpoints, with the data
being used to draft national guidelines.
There are countless hypertension sufferers in thedeveloped nations and each country has its own guidelines.
In Japan, the first Guidelines for the Management ofHypertension were issued in 1990 through collaboration
between the Ministry of Health, Labour and Welfare and theJapan Medical Association (19). After that, the JapaneseSociety of Hypertension (JSH) spearheaded the Hypertension
Treatment Guidelines published in 2000, with revised
editions released in 2004, 2009 and 2014.
In the United States, the guidelines came in 1977 in theform of JNC-1, or the First Report of the Joint National
Committee on Prevention, Detection, Evaluation, andTreatment of High Blood Pressure. This document mentions
the definitions of normal blood pressure and hypertension,
the risk factors for hypertensive patients, assessment fororgan dysfunction and other complications and specifictreatment guidelines.
In terms of the changes in first-line treatment for
hypertension, JNC-1 and JNC-2 (1980) only mentioned

Systematized Survey on the History of Drug Discovery with Technical Development

87

88

thiazide diuretics, while JNC-3 (1984) included both thiazide
diuretics and β-blockers. In addition to these, JNC-4 (1988)

for first-line treatment for hypertensive patients withoutcomplications, instead listing the names of anti-hypertensives

also included calcium channel blockers and ACE inhibitors.
However, JNC-5 (1992) went back to thiazide diuretics andin order of usage frequency in Japan and opting for the mostappropriate drug for the age and gender of the patient.

β-blockers as first-line treatments, with ACE inhibitors,
calcium channel blockers and α-blocker as substitutes for

JSH-2009 designates five first-line treatments, namely
diuretics, β-blockers (including α/β-blockers), calcium

patients unable to undergo the first-line treatments. In JNC-6(1997) the policy changed to select the anti-hypertensive

channel blockers, ACE blockers and ARBs, and does notrecommend α-blockers. Beta-blockers are listed as first-line

treatment most expected to be beneficial, while limiting theuse of diuretics and β-blockers as first-line treatment totreatment with the condition that they are “not necessarily the
first-line treatment of choice for elderly patients without

patients with no complications.
The WHO guidelines WHO/ISH 1989 and WHO/ISH

complications or patients with glycolipid metabolism
abnormalities”. While diuretics are the cheapest of these

1993 were published the year after JNC-1 and were limited
to mild hypertensive patients. This was due to the idea thatdrugs in Japan, they are emphasized as concomitant drugs
due to concerns over hypokalemia, abnormal glucose

80% of patients were mild hypertensive patients for whom
the course of medication was significant.

tolerance, hyperuricemia and the impact on fat that
accompanies thiazide diuretics, as well as the fact that they

According to these guidelines, there were five first-line
treatments: diuretics, β-blockers, ACE inhibitors, calcium

lose more of their hypotensive effect as the dosage decreases.
JSH-2014 recommends four first-line treatments: diuretics,

channel blockers and α-blockers (21). This was quite different
from the American guidelines.

calcium channel blockers, ACE inhibitors and ARBs.
Although β-blockers are still one of the main

According to Kikuo Arakawa, “In the 5th report of the
JNC, the United States suddenly started to demand evidenceanti-hypertensives, they have been deemed less effective
than other drugs in terms of preventing cerebral hemorrhage,(Note 9)for each drug, giving priority approval to diuretics andβ-blockers as having a sufficient accumulation of evidence,

particularly in light of evidence from overseas, and havebeen excluded from first-line treatments for patients without

while other drugs were limited to cases where these could
not be used. This gave rise to a great deal of discussion

complications. However, they are “actively applied” forpatients with heart disease complications. The stance takenworldwide” (22). Thus, there was a significant difference fromthe WHO guidelines that made use of six types of drugs.

by the Japanese guidelines seems to be the right choice.
Evidence is confirmed by large-scale clinical studies. In

Unclarified issues and inconsistencies were also identified interms of whether adequate controls had been in place in past

relation to hypertension, research materials by Hisaichiro
Tsukiyama and Keiko Otsuka et al. (4:113-142) include reports

trials of the diuretics and β-blockers mentioned in JNC,
leading to the idea of reconsidering evidence.

worldwide from 80 large-scale clinical trials on hypertension
in the 1990s alone.

Discussion arose in 1995 over the safety of calcium
channel blockers, with reports from several clinical trials

There are very few cases featuring the true endpoints ofmortality rate and major disease onset; it is not easy toidentifying risks. Despite many reported results to thecontrary, JNC-6 still approved the use of calcium channel

demonstrate whether there is a statistically significant
difference between the administration group and theblockers, although it did restrict the use of short-acting
calcium channel blockers, recommending their long-acting

non-administration group (the group administered theplacebo instead of the actual drug). Accordingly, it has notcounterparts instead.
JNC-7 (2003) emphasized cost effectiveness, deeming

been uncommon for clinical trials to produce different results
even when similar trials are repeated.

diuretics to be the best form of anti-hypertensive andpresenting these as first-line treatment. JNC-8 (2014) offers

The protocols used in these trials vary for each trial. There
are also inevitable differences between trials in terms of thecalcium channel blockers, ACE inhibitors, ARBs anddiuretics as first-line treatments, although priority is given to

backgrounds of the patients being administered the drugs, inother words, different genes, different disease histories anddiuretics from the perspective of cost.
WHO/ISH 2003 clearly places diuretics as first-linedifferent attitudes toward taking medicine. In order to obtainrepeatable results, the conditions have to be as identical astreatment in all risk categories for the same reason. However,given the reality that in many cases hypertensive patients

possible with the parameters increased. Althoughmeta-analyses are conducted for that purpose, it is difficult toneed to take a number of different drugs concomitantly, theseguidelines adopt the stance that “it is meaningless toinclude the results of all clinical trials carried out under
different protocols and points of doubt still remain. It may bedesignate or emphasize a first-line treatment”.
The Japanese guidelines fundamentally support the WHOtime to reconsider the sense in conducting large-scale trials
to obtain evidence. Despite this evident difficulty withidea, with JSH-2004 offering no fixed order of precedence

clinical trials, the number of large-scale clinical intervention

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchtrials has still continued to grow since the year 2000.
Non-clinical studies determine medicinal efficacy using

angiotensin II production. See Fig. 4.10.
Note 9: Theory-based clinical trial results

animal experiments. Rodents (rats and mice) used inexperiments are germ-free animals from pure strains in order

References

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Fishberg, A. M.: Hypertension and Nephritis. Fifth
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Shionoiri H. (ed.): Kōketsuatsu no Igaku (Medical
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enough experiments on live organisms, it is even moredifficult to align conditions for pathological animals.

[3]

Veterans Administration Cooperative Study Group on

One can easily guess that this difficulty is multiplied in
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Antihypertensive agents: Effects of treatment on

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[4]

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by Kyushu University.
*: The Hisayama Study -- A highly-detailed, non-interventional
epidemiological study on lifestyle-related diseases conducted by
Kyushu University Graduate School of Medical Sciences (Prof.
Yutaka Kiyohara) and the people of Hisayama-cho in Fukuoka(population 8,400) since 1961, gathered significant amounts of
epidemiological data. A high postmortem autopsy rate has ensured
very accurate data, with 99% of residents tracked. Source: Websiteof the Department of Environmental Medicine, Kyushu University
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Hiwada K. (ed.): Kōketsuatsu Kenkyū no RekishiŌtuska Keiko (History of Hypertension Research
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[5]

Fleckenstain A., Kammermeier H., Doring H.: Zum
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mit gleichzeitig Sauerstoffeinsparenden,
Myokard-Effekten, Prenylamin und Iproveratril. Z.
Kreislaufforsch 56: 716-744, 839-853 (1967).

[6]

Murakami M. et. al.: Antihypertensive effect ofNifedipine, a new coronary dilator. Japanese Heart
Journal 13 (2): 128-135 (1972).

[7]

Tanabe Seiyaku 330-nen Tsūshi (330-year History of
Tanabe Seiyaku). Tanabe Seiyaku Co., Ltd. 50 (2007).

[8]
Note 3: Clinical intervention trial -- Deliberately setting andcontrolling trial conditions relating to the treatment, lifestyle andbehavior of study participants.

Sato M., Nagao T., Yamaguchi I. et al.:Pharmacological studies on a new
1,5-Benzothiazepine derivative. ArzneimittelforschungNote 4: The loop of Henle is the name of a portion of the uriniferous
tubules at the point where the uriniferous tubules passing through thekidneys form long loops. See Fig. 4.8.
Note 5: While some are clearly distinguished by their mechanism ofaction, others were named according to a marketing strategy.
Generally speaking, not all first-generation or second-generation
drugs can necessarily be clearly defined.

21: 1338-1343 (1971).
[9]The Multicenter Diltiazem Post-infarction Trial
Research Group (MDPIT): The effect of diltiazem on
mortality and re-infarction after myocardial infarction,
New England Journal of Medicine 319: 385-392(1988).

[10] Saruta T., Hiwada K. & Ogihara T.: Ca Kikkōyaku no
Note 6: World Health Organization (WHO); International Society ofHypertension (ISH)

Subete (All about Ca Antagonists). Sentan Igaku-sha
24-28 (1999).

Note 7: The Joint National Committee (JNC) on Hypertension[11] Yanagisawa T.: (Me de Miru Junkkankibyō Shirīzu

Note 8: Angiotensin I is converted into angiotensin II not only by
ACE, but also by chymase, an enzyme secreted from the mastocytes
in the event of tissue damage. There are also other routes to13) Junkankibyō no Yakubutsu Ryōhō: Ca Kikkōyaku
no Seibun to Sayō Kijo ([Visual cardiovascular disease

Systematized Survey on the History of Drug Discovery with Technical Development

89

series 13] "Drug therapy for cardiovascular diseases":components and action mechanisms of Ca antagonists).
Medical View 132-143 (1998).

(2002).
[23] Product details taken from the drug interview forms
from the various companies.

[12] Pahor M., Guralnik J.M., Ferrucci L., et al.: Calcium
channel blockade and incidence of cancer in aged
populations. Lancet 348: 493-497 (1996).

4.3 Medications for Hyperlipidemia(Hyperlipidemic Drugs)[13] Staesen J.A. et al. Randomized double-blind
comparison of placebo and active treatment for older
patients with isolated systolic hypertension. Lancet
350: 757-764 (1997).
[14] Gong L., Zhang W., Zhu Y. et al.: Shanghai trial of
nifedipine in the elderly (STONE). Journal ofHypertension 14: 1237-1245 (1996).
[15] Jick H. et al.: Lancet 349: 525-528 (1997).
[16] Ad Hoc Subcommittee of the Liaison Committee ofthe World Health Organisation and the International
Society of Hypertension: Effects of calcium
antagonists on the risks of coronary heart disease,cancer and bleeding. Journal of Hypertension 15:
105-115 (1997).
[17] Arakawa K., Maruta H.: Ability of kallikrein to
generate angiotensin II-like pressor substance and a
proposed ‘kinin-tensin enzyme system’. Nature 288:705-706 (1980).
[18] Arakawa K., Urata H.: Hypothesis regarding thepathological role of alternative pathway of angiotensin
II formation in atherosclerosis. Hypertension 35:
638-641 (2000).
[19] Ministry of Health, Labour and Welfare / Japan
Medical Association: Kōketsuatsu Shindan no Tebiki(Hypertension Diagnosis Manual). Japan Medical
Journal, Tokyo (1990).
[20] Japanese Society of Hypertension Committee for
Guidelines for the Management of Hypertension:
Guidelines for the Management of Hypertension 2004.
Japanese Society of Hypertension, Tokyo (2004).
[21] WHO Expert Committee: Arterial Hypertension.
Technical Report Series No 628. Geniva, World
Health Organization (1978).
[22] Kōketsuatsu Kenkyū no Rekishi (History ofHypertension Research). Hiwada K. (ed.), Arakawa

90

According to the 2011 Patient Survey conducted by the
Ministry of Health, Labour and Welfare, the total number ofhyperlipidemia sufferers (patients assumed to be receiving
ongoing treatment) was 1.89 million (530,000 males and1.36 million females). The actual number of people withhyperlipidemia but not receiving ongoing treatment isassumed to be several times higher. As one of the causes ofmetabolic syndrome, hyperlipidemia has even frequently
been featured on television; there is now very high publicknowledge and awareness of this disease, including good andbad cholesterol. However, hyperlipidemic drugs described ashaving a hyperlipidemic effect started being used in the
1990s; and new drugs that actually lowered cholesterol levels
emerged around 1990, as did those for other lifestyle-relateddiseases.
This section begins by tracing the history of
hyperlipidemia, including cholesterol and triglycerides.
In 1908, Russian pathologist Nikolay Nikolaevich
Anichkov observed atherosclerosis in the arterial walls of
rabbits that had been given cholesterol. Examination of thelesion sites confirmed the accumulation of macrophages,
lymphocytes and smooth muscle myocytes. Anichkov also
reported on the relationship between cholesterol andatherosclerosis, stating that “there is no atherosclerosis
without cholesterol”. In 1930, he came to Japan and evenlectured at the International Academy of Pathology in Osaka.
However, the prevailing idea at the time was that
arteriosclerosis occurred spontaneously with age. Anichkov’s
theory was not well received by the American medical
circles and the rest of the academic world, since humans andrabbits were different species (1, 2).
Forty years on, in the 1950s, it was found that almost halfof the deaths in the United States were due to coronary arterydisease, particularly angina pectoris and myocardial
infarction. John William Gofman of the University ofCalifornia at Berkeley re-examined Anichkov’s theory using
the most advanced technology available at the time andreported that cholesterol exists in the blood as very
low-density lipoprotein (VLDL), low-density lipoprotein(LDL) and high-density lipoprotein (HDL), that LDL
increases with a high fat diet and that VLDL increases with aK.: Kōketsuatsu Chiryo Gaidorain (Guidelines for thehigh carbohydrate diet (3).
While the relationship between cholesterol andManagement of Hypertension). Sentan Igaku-sha 150

arteriosclerosis started gaining some attention at this time,

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchmost of the research was to do with cholesterol in the diet.
American dietician Ancel Keys noted a relationship between

biomarkers. Many of the results from the Framingham Heart
Study have matched the experience-based opinions ofheart disease and lifestyle and began researching this fromthe 1940s onwards. In 1955, he made the novel proposal toclinicians. With these momentous results providing a wealthof knowledge on analyzing and managing heart disease, theconduct a scientific, continuous study on the relationshipbetween cholesterol and heart disease by means of a

Framingham Heart Study has had a very significant role toplay.

large-scale epidemiological study focusing on therelationship between diet, lifestyle and heart disease.

Cholesterol and triglycerides in the blood do not exist in
isolation; they bond with proteins to form lipoprotein.

Consequently, the “Seven Countries Study” began in 1958,
with seven countries taking part, including Japan, to clarify

Donald S. Frederickson applied the idea of lipoprotein
clinically and discovered a number of apoproteins. He was

the relationship between cholesterol and heart disease. Aspart of this research, the “Mediterranean diet”, which is low

able to categorize abnormal cholesterol levels by theapoprotein level. Frederickson’s categorization ofin animal fat, was reported to curb heart disease, while dietshigh in animal fat were reported to increase heart disease.

hypercholesterolemia is known as the FredericksonClassification; it was adopted by the WHO in 1971 to

Although this study had many inadequacies by today’s
standards, it has merit as an epidemiological study in being

become the international classification system (7).
Meanwhile, Joseph Leonard Goldstein and Michael Stuart

the first to investigate the relationship between lifestyle andheart disease. The study also examined the relationship

Brown were working on clarifying cholesterol metabolism.
In addition to discovering that hepatocytes have LDL

between obesity and heart disease, the importance of exercise
and the relationship between hypertension and cerebral

receptors, Goldstein and Brown also examined theirrelationship to genetic diseases and proved that in the event

hemorrhage (4, 5) (Note 1).
In 1948, the USPHS National Heart Institute selectedof familial hypercholesterolemia (FH), cholesterol is notabsorbed into the liver and increases in the blood due to a

Framingham, Massachusetts, a town of 28,000 people, as thetarget for a large-scale prospective epidemiological cohort

lack of LDL receptors. They were jointly awarded the Nobel
Prize in Physiology or Medicine in 1985 “for theirstudy. Although basic research was being conducted in the
United States at the time to examine the rise of coronary

discoveries concerning the regulation of cholesterol
metabolism”.

artery disease (ischemic heart disease) and how to deal withit, this was the Framingham Heart Study, which has

Goldstein and Brown’s hypothesis that heart disease iscaused by high cholesterol required evidence that reducing

continued to this day (6). Since the risk factors for heartdisease were not known at the time, the aim was to examine

LDL could prevent arteriosclerosis, thereby preventing heartdisease and cerebral hemorrhage. Cholesterol-lowering

which risk factors were involved in coronary artery disease
and to what extent. The risk factors selected were smoking,medications in clinical use at the time included
cholestyramine to lower cholesterol levels, fibrates to lower

hypertension, cholesterol and glycosuria, as well as ageing.
Bloods taken were cryopreserved for future research.

triglyceride levels and niacin to lower HDL levels. No
medications had yet been developed to significantly reduce

This study is said to have be initiated to clarify the causeof President Roosevelt’s death, as he had died of cerebral

the level of cholesterol most commonly observed inarteriosclerosis lesions. Cholestyramine was selected for thishemorrhage despite having used a dietary treatment for his
hypertension (see Section 4.2. Medications for Hypertension

purpose and the Coronary Primary Prevention Trial (CPPT)
was commenced in 1971 by the Lipid Research Clinics of theabove).
More than 1,000 reports have been published from the

National Heart, Lung, and Blood Institute (NHLBI). The trial
was a double-blind primary prevention trial (a clinical trial

Framingham Heart Study. Major progress reports from the
1960s report that “smoking, hypertension, high cholesterol

examining the extent to which initial event occurrence issuppressed in people with no medical history of ischemic

and obesity are risk factors for heart disease” and that“exercise reduces the risk of disease”. In the 1970s, it washeart disease). Coronary heart disease was clearly confirmed
to have decreased in the patient group whose blood

reported that “hypertension increases the risk of cerebral
hemorrhage” and that “stress increases the risk of heartcholesterol levels had been lowered with the use ofcholestyramine (8). This result was published in 1980,

disease”. In the 1980s, it was found that “HDL curbs heartdisease”, while in the 1990s it was reported thatcausing the medical world to acknowledge that high blood
cholesterol increases the risk of ischemic heart disease.

“hypertension, smoking, glucose intolerance and highcholesterol combine to increase the risk of heart disease”. In

However, although cholestyramine lowered the risk ofcoronary heart disease in patients with arteriosclerosis, nothe 2000s, advances in genetic research resulted in reports on
the relationship between genes and heart diseases, as well as

significant difference was found between that group and theplacebo group in terms of the overall mortality rate. A

the relationship between heart disease and various

number of large-scale interventional secondary prevention

Systematized Survey on the History of Drug Discovery with Technical Development

91

trials (clinical trials examining the extent to which repeat
event occurrence is suppressed in people with a medical
history of ischemic heart disease) were conducted in the
1970s and 1980s using clofibrate, niacin and EPA, but nosignificant difference in overall mortality rate was founddespite lower total cholesterol levels (See Table 4.1).
Table 4.1 Pre-Statin Interventional Trials

Secondary
prevention trial

Primary
prevention trial

Name of trial

Drug

No. of cases(capita)
control/administration

Duration(years)TC

Mortality
rate (%)

Year
published%Heartdiseaseonset rate(%)

TC
(pretreatment) (reduction

rate)

mg/dl

WHO

Clofibrate

5,331/5,296

5.3

250

∆9

∆20

+22

1978

LRC-CPPT

Cholestyramine

1,906/1,900

7.4

292

∆13

∆19

NS

1984

Helsinki Heart
Study

Gemfibrozil

2,051/2,030

5

270

∆9

∆34

NS

1987

VA Drug

Niacin

45/83

5

246

∆4

NA

CDP

Niacin1,119/2,789

6.2

250

∆10

∆34

NS

1975

Clofibrate

1,103/2,789

6.2

250

∆6.5

NS

NS

1975

EPA

1,015/1,018

2

NA

NA

NS

∆29

1989

DART

1974

Source: The Journal of the Japanese Society of Internal Medicine 98 (9): 281-290 (2009). NS: Not Significant

After around a decade of inactivity, large-scaleinterventional trials on hypercholesterolemia were resumed.
The leading role of this new generation was taken up by
statins, which have a powerful cholesterol-lowering effect.
Many of the secondary prevention trials showed two-digit
decreases in total cholesterol levels, which had not beenachieved with previous drugs, as well as a significant
improvement in major blood vessel events occurrence andoverall mortality rate. With the powerfulcholesterol-lowering effect of statins demonstrated to lower
the overall mortality rate, statins gained a very firm footing
as cholesterol-lowering medications.
Table 4.2 Statin Interventional Trials
Name of trial

Drug

No. of cases(capita)
control/administration

DurationTC(years) (pretreatment)

mg/dl

TC
Heart
Mortality(reduction disease rate (%)rate)
onset rate
%
(%)

Year
published

Secondary
prevention trials
4S

Simvastatin

2,221/2,223

5.4

261

∆25

∆34

∆30

1994

CARE

Pravastatin

2,081/2,078

5

209

∆20

∆24

NS

1996

LIPID

Pravastatin

4,512/4,502

6.1

218

∆18

∆24

∆22

1998

Statinmeta-analysis

Statins

45,054/45,002

4.7

∆23

∆12

2005

In the 1990s, further clarification was made on theformation mechanism of arteriosclerosis; further clarification
was also made on the function of oxidized LDL andmacrophages. Fig. 4.13 shows how arteriosclerosis occurs.
The initial risk factors for vascular endothelial cell damage
are known to include hypertension, hyperglycemia, ageing,smoking and oxidation; once damaged, LDL accumulates in
the intima and is degenerated by reactive oxygen (superoxide,hydroxy radicals, hydrogen peroxide and singlet oxygen)produced by the endothelial cells. Monocytes then penetrate
the intima and are activated to become macrophages, which
consume the oxidized and degenerated LDL. Thesemacrophages have scavenger receptors, which absorb
oxidized LDL indefinitely, eventually turning into foam cells
laden with cholesterol ester. Cholesterol ester accumulates in
the lining membrane, where it forms plaque.
The platelets eventually adheres to the plaque, after whichthrombi are formed by the action of the blood coagulation
system, leading to infarction.
Although hyperlipidemia encompasses
hypertriglyceridemia as well as high cholesterol, the focus
has historically been on hypercholesterolemia in relation toarteriosclerosis. In recent years, some attention has begun tobe paid to research examining the impact of triglycerides onarteriosclerosis. HDL is known to be capable of extracting
the cholesterol in atherosclerotic plaque and sending it to theliver; however, increased VLDL including triglycerides
reduces HDL. Increased VLDL is also known to convert
LDL into small LDL and increase the amount of remnant
degraded lipoproteins. Small LDL is also easily
phagocytized by remnant lipoproteins and macrophages,
which then advances the atherosclerotic effect. Reports also
indicate that triglycerides increase the viscosity of the bloodand aggravate inflammation.

Source: The Journal of the Japanese Society of Internal Medicine 98 (9): 281-290 (2009). NS: Not Significant

Foam macrophages
Macrophages absorbing LDL
Platelets
Red blood cells

Cholesterol
Thrombus

Monocytes penetrate themembrane

92

Normal bloodvesselNo damage toendothelial cells

Endothelial cells
damaged by risk
factors overloading theblood vessel

LDL becomes oxidized LDL when
the lining membrane is penetrated
Monocytes/macrophages
phagocytize LDL
Cholesterol builds up andatherosclerosis (atheroma) occurs

Cholesterol deposits thicken
the lining membrane
Plaque breaks off to form
thrombi, resulting in infarction

Source: Umezu 2014

Risk factors:
Ageing, oxidation,
hypertension, hyperglycemia,
smoking, LDL

Oxidized LDL, monocyte
migration
Macrophage phagocytosis effect

Platelet activation
Thrombus formation

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchFig. 4.13 Causes of Arteriosclerosis
The following sections provide an outline of the history of
hyperlipidemia drugs discovered in the course of clarifying
the relationship between arteriosclerosis and hyperlipidemia.
4.3.1.

drug.
4.3.2.

Natural Hyperlipidemia Medications

The first hyperlipidemic drug to be developed in Japanafter the Second World War was polysaccharide dextran

Niacinsulfate ester (MDS Kowa®) by Kowa Kagaku (now Kowa

Niacin is the generic term for nicotinic acid andnicotinamides. It is a water-soluble vitamin-B complex, isPharmaceutical). According to the centennial history ofalso known as vitamin B3, and is a nutrient essential to theKowa, “until then, heparin had been used as a hyperlipidemic

metabolism of carbohydrates, lipids and proteins. Itsdrug, but it had the drawback of being ineffective when taken

lipid-lowering effect has been known since the 1950s and it

orally and tended to cause bleeding with prolonged

has been used clinically in the United States. With the idea

administration. To combat this, Professor Kozo Yamada of

emerging at the time that LDL is bad and HDL is good,the Nagoya University School of Medicine proposed andCoronary Drug Trials were carried out between 1965 anddeveloped polysaccharide dextran, which is structurally

1974 to prove that HDL is good. Niacin was approved by thesimilar to heparin”. It was confirmed to have low toxicity

FDA as the best HDL-increasing agent available at the time;and a cholesterol-lowering effect. It was launched on the

however, its most potent beneficial factors could not bemarket in 1963 (10). It is still being used in

identified, while the results found that it lowered both LDL

hypertriglyceridemia treatment, with recent research showing

and triglycerides(9)

that it activates serum lipoprotein lipase (LPL) and hepatic.

Niacin lowers the LDL-cholesterol and VLDL levels in

triglyceride lipase (HTGL) and reduces triglycerides in the
blood.

patients with hyperlipidemia, while also increasing the
HDL-cholesterol, thereby allowing good control over blood

In 1974, Ajinomoto and Morishita Pharmaceuticallaunched the hyperlipidemic drug soysterol. Soysterol is anlipid levels, although its effects are mild.
The mechanism of action of niacin was unclear at the time.

extract containing 40-50% plant sterols and 18-22% natural
tocopherols. Sterols have a cholesterol-lowering effect byRecent basic research has reported that niacin inhibits
lipolysis in adipose tissue, the main source of free fatty acidsin the blood. Although the liver produces triglycerides (TG)from free fatty acids, nicotinic acid lowers the triglyceride
levels, which in turn lowers the VLDL concentration,

integrating into the biliary micelles in enterohepatic
circulation and competitively inhibit the ingestion of animal
fat cholesterol in the digestive tract, thereby lowering thecholesterol level, as well as promoting the catabolic
excretion of cholesterol. Currently, they are also utilized as

thereby lowering the LDL concentration in the blood.

food for specified health uses (FOSHU).

Later research also reported that niacin increases the

Epidemiological studies in the 1970s found that thesecretion of plasminogen activators (t-PA), lowers theindigenous Inuit of Greenland, with a staple diet of seals andconcentration of plasma fibrinogen and restores theother marine life, had a far lower heart disease mortality rate

endothelial function of endothelial cells damaged fromthan Danish Caucasians. The blood of these indigenous

atherosclerosis. However, none of these effects are very

people was found to contain high concentrations of

powerful.

eicosapentaenoic acid (EPA), which is found in ample supply

In 1968, while researching nicotinate ester, researchers atin the blubber of seals and other animals. EPA began to gain

Swedish company Bofors discovered the prodrug niceritrol,

attention. In Japan, epidemiological studies were carried out

which is absorbed into the body and hydrolyzed into

in places such as Chiba Prefecture and the township ofnicotinic acid. In 1970, Sanwa Kagaku Kenkyusho licensed

Kumihama in Kyoto Prefecture, confirming that EPA has a

the technology from Bofors and adapted it forsecondary prevention effect for ischemic heart disease.

hyperlipidemia, launching it on the market in 1982.

Mochida Pharmaceutical eventually obtained approval for
EPA as a pharmaceutical product due to its efficacy in

An entirely-Japanese niacin prodrug, nicomol (Kyorin
Pharmaceutical), was also launched on the market; it was“alleviating ulcers, pain and cold sensation accompanying

selected for manufacturing approval in 1971 from among 65

arteriosclerosis obliterans”. In 1994, this was appended tonicotinic acid derivative products. Yoshitomi Pharmaceuticalinclude its efficacy against hyperlipidemia (see 4.4. Drugs

also launched its own nicotinic acid derivative productthat Act on the Blood System). A large-scale randomized

pronicat in 1972, although it was indicated forcontrolled trial, the Japan EPA Lipid Intervention Studyarteriosclerosis obliterans rather than as a hyperlipidemic(JELIS), was conducted in 1996 to examine the coronary

Systematized Survey on the History of Drug Discovery with Technical Development

93event inhibitory effect of prolonged administration ofeasily-ingested prodrugs. Around 1980, it was deemed tohigh-purity EPA to Japanese hyperlipidemia patients. The

have a HDL-cholesterol increasing effect and began to be

results were published in 2007 and indicated that coronary

introduced overseas (17).

artery disease is preventable (Note 2). After that, other foods for

In 1981, Sumitomo Chemical (now Dainippon Sumitomo

specified health uses (FOSHU) with similar ingredients were

Pharma) developed clinofibrate. However, fibrate sales

also launched on the market.

dropped away due to poor cholesterol-lowering efficacy and

The results of the DART Study also demonstrate aissues with side effects. After that, however, products begansignificant improvement in overall mortality rate among theto emerge with powerful TG-lowering effects as well as

EPA administration group (see Table 4.3.1).

HDL boosting effects, the so-called second generation.

A report by Studer et al. states that the only two drugs tohave demonstrated a difference in improving overallmortality rate are statins and EPA

(11)

.

Backed by basic research on the involvement of TG inarteriosclerosis, bezafibrate (developed by Kissei
Pharmaceutical, discovered by Boehringer Ingelheim, now
Roche) was introduced in Japan in 1991. In 1999, approval

4.3.3.

Fibrate Lipid-Lowering Drugs

Fibrates have a long history as hyperlipidemic drugs. In

ASKA Pharmaceutical; licensed from FournierFrance in 1953, a candidate compound was found that had a

Pharmaceuticals and jointly marketed with Kaken

confirmed effect both on rats and clinically. This drew the

Pharmaceutical) due to its benefit of once-a-day

attention of British company Imperial Chemical Industries

administration in addition to its TG-lowering effect.

(ICI), whose researchers used screening on rats to produce a

The liver contains peroxisome proliferator-activatedcompound with a powerful anti-cholesterol effect and low

receptors (PPAR) that regulate lipid metabolism and belong

toxicity in 1962. This compound was clofibrate

to the nuclear receptor superfamily. PPAR-α regulates the(ethyl-α-4-chlorophenoxyisobutyrate)(12). While its

expression of genes involved in the structure and function of

mechanism of action was initially unknown, experiments onlipoproteins, but when ligand fibrates bond with PPAR-α,rats and clinical trials confirmed its VLDL and LDLtranscription is initiated. This promotes the expression oflowering effects. It was reported as acting strongly on VLDL

lipoprotein lipase (LPL) and accelerates the catabolism ofand less strongly on LDL. There were later concerns about

VLDL and chylomicrons. This also inhibits the expression ofside effects as it was found that prolonged administration toapolipoprotein C-II, the TG core, lowering its concentration

rats caused hypertrophy of the liver and peroxisome

and thereby lowering the TG levels. Conversely,

proliferation. However, it was deemed that the peroxisome

apolipoprotein A-I and A-II expression increases, while HDL

proliferation and the lipid-lowering effect were due toalso increases. This effect is presumed to lower thedifferent mechanisms; the drug was approved by the FDA in

triglyceride levels and cause a reduction in VLDL

1967 and was used in the United States as a hyperlipidemic

concentration.

drug. Clofibrate was approved in Japan in 1965.
Attention was again drawn to the cancer risk of fibrates as

Meanwhile, Japanese researchers have found fibrates tohave another mechanism than lowering lipids. In 1975,a result of chronic toxicity testing in rats. Further

researchers at Takeda Pharmaceutical found during screening

experiments confirmed that the onset of cancer was athat when a clofibrate derivative was administered to aphenomenon unique to rats and would not occur in primatesdiabetic mouse model, it not only lowered the lipid levels,(13, 14)

but also lowered the blood glucose levels. This was further.

Gemfibrozil and fenofibrate were later used in the UnitedStates, while bezafibrate and ciprofibrate began to be
These fibrates were also confirmed to be accompanied bya similar peroxisome proliferation phenomenon; this waslater found to be a triglyceride-lowering mechanism related
to the PPAR receptors

refined to produce the diabetes drug ciglitazone (18, 19).
Ciglitazone was found to act on PPAR-γ in the PPAR
family, demonstrating a hypoglycemic effect, and gainedprescribed in Europe.

(15, 16).

Progress was made on fibrate research and development in94

was granted for fenofibrate (Grelan Pharmaceutical, now

much attention as a diabetes drug (see 4.1.6. Thiazolidine
Derivatives).
Bezafibrate was also found to act on PPAR-γ, which is
involved in insulin resistance, unlike other fibrates. Thissuggests the possibility of using PPAR-γ stimulation to

Japan, with Yoshitomi Pharmaceutical (now Mitsubishi

directly improve insulin resistance. Several controlled

Tanabe Pharma) obtaining approval for its own product,clinical trials have been conducted on insulin resistancesimfibrate, in 1971. Whereas clofibrate was oil soluble, thisusing bezafibrate and a placebo, with the administration

was produced in easily-administered solid formulationsgroups showing greater suppression of increases in insulin(capsules, granules), marking the beginning ofresistance than the placebo groups, as well as significantly

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchlower primary endpoints of fatal and nonfatal myocardial

4.3.4.

infarction and sudden death (20).
More side effects have been reported from fibrates than

Digestive Tract Lipid Absorption Inhibitors(Anion-Exchange Resin)

Cholestyramine is an anion-exchange resin developed byfrom statins, including the breakdown of skeletal muscle

Merck in the 1960s. Merck initially developed the drug

tissue and rhabdomyolysis, in which necrosis causes theunder the brand name Cumid® as a treatment for pruritus

release of cell components, as well as renal dysfunction,

associated with biliary cirrhosis. This research was later

headaches and nausea. Fibrates also have a less potent

taken over by Mead Johnson Nutrition, which developed it ascholesterol-lowering effect than statins, which have a very
powerful cholesterol-lowering effect. Accordingly, whena cholesterol-lowering drug under the brand name Questran®
(21:140)

statins appeared, they were expected to take over the market.
However, the impact of triglycerides aside from cholesterol
in arteriosclerosis has also drawn some attention, allowing
fibrates to begin to be differentiated from statins due to their.

As a polymer, it is not absorbed into the body even whenadministered orally; rather, it binds with negatively-charged
bile acid in the small intestine. The bound bile acid is thenexcreted with the feces. Bile acid is naturally repeatedly

superior triglyceride-lowering effect.
Fig. 4.14 shows the chemical structures of representative

reabsorbed into the liver through enterohepatic circulation.

hyperlipidemic drugs with different mechanisms of action.

When it is excreted from the body with the anionic-exchange

The distinguishing characteristics of the efficacy of eachresin, less bile acid is reabsorbed by the liver. This isdrug are given in Table 4.3.

detected by the liver cells and more bile acid is produced.
Since bile acid is synthesized from cholesterol, increased bile

NiacinProbucolacid production means lower cholesterol levels in the liver
cells. To compensate for the reduced amount of cholesterol,the LDL receptors on the surface of the liver cells increase;
the LDL in the blood then binds to the LDL receptors and is

Created by Marion Merrell Dow
Marketed by Otsuka Pharmaceuticaland Daiichi Pharmaceuticalabsorbed by the liver cells, resulting in a reduction of

Fibrates

LDL-cholesterol in the blood. For details, see Fig. 4.15.
Even Goldstein and Brown used ion-exchange resin in
Clofibrate

their cholesterol metabolism experiments. The drug was also

Bezafibrate(Boehringer Ingelheim)

used in the Lipid Research Clinics Coronary Primary
Prevention Trial (LRC-CTTP) (8), a well-known clinical trialthat first proved that lipid-lowering treatments prevented
ischemic heart disease. In this trial, theClinofibrate(Sumitomo Chemical)

Simfibrate (Yoshitomi Pharmaceutical)

cholestyramine-administered group experienced a 13.4%
Fig. 4.14 Chemical Structures of Hyperlipidemic Drugs

reduction in total cholesterol and a 20.3% reduction in
LDL-cholesterol. The primary endpoints of death from heartdisease and onset of ischemic heart disease were curbed by

Table 4.3 Efficacy of Hyperlipidemic Drugs

19%.
LDL cholesterol Totalcholesterol
StatinsIon-exchange
resin





Fibrates

Nicotinics

Probucol



EPA

-

Triglycerides HDL
Main drugs (genericcholesterol name)

Cholestyramine was expected to have no serious sidePravastatin
Rosuvastatin

effects and a clear cholesterol-lowering effect. It was-Cholestyramine
Colestimide

launched in Japan in 1985 by Bristol-Myers, but was met





Bezafibrate
Fenofibratewith low patient compliance due to the high dosage of 8-12g



Tocophenol nicotinate



-



Probucol--per day and the presentation of gastrointestinal side effects,
including constipation and bloating. There was demand for a

Eicosapentaenoic
acid ester

: lowered 25% or more : lowered 20-25% : lowered 10-20%
: increased 10-20% : increased 20-30%-: 10 to -10%
Source: Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017,
Japan Atherosclerosis Society

new drug with a lower dosage amount.
Mitsubishi-Tokyo Pharmaceuticals (Current Mitsubishi
Tanabe Pharma) launched the improved drug colestimide inJapan in 1999. A copolymer of 2-methylimidazole andepichlorohydrin, it demonstrated superior bile acidabsorption activity. It was easily ingested in the form of a pillcoated with a cellulose base and did not need to be dissolved

Systematized Survey on the History of Drug Discovery with Technical Development95

in water as did cholestyramine. It also had a low dosage at
3-4g per day.

4.3.5.

Probucol

Probucol is a bisphenol compound synthesized by the

Since it had a different mechanism of action from other

Consolidation Coal Company of the United States as an

drugs, it could be taken concomitantly by patients showing

antioxidant and later researched and developed by the Dow

poor cholesterol-lowering effects, although many patients

Chemical Company. It has an antioxidant effect and awere still concerned about the dosage.

specific total serum cholesterol lowering effect. Clinical

In 1983, Sumitomo Chemical launched melinamide, atrials of it began in the United States in 1968 and it was

drug that inhibits the absorption of dietary cholesterol byreleased on the market in 1977 following FDA approval. In

inhibiting the function of cholesterol esterase, which

Japan, Dow Chemical Japan started working on jointhydrolyzes cholesterol ester in the digestive tract, anddevelopments with Otsuka Pharmaceutical and Daiichi

inhibiting acyl-CoA cholesterol acyl transferase (ACAT),

Pharmaceutical in 1979, with Daiichi launching Sinlestal® inwhich esterifies cholesterol in the intestinal mucosal cells.

1985 and Otsuka launching Lorelco® the same year.

Later, American company MSD developed ezetimibe, a

These drugs slightly lower the LDL level, which in turndrug that inhibits the absorption of cholesterol and plant

lowers the cholesterol level in the blood. While some areas

sterol from the digestive tract, and launched it in Japan inof this mechanism of action are still unclear, these drugs act

2007. The drug is reported as inhibiting 58% of cholesterol

to promote the catabolism and excretion of cholesterol into

absorption compared to a placebo group. While there were

bile acid, as well as inhibiting cholesterol biosynthesis.

issues with the high dosage of anionic-exchange resin,

Particular attention has been drawn to the antioxidant effect,

ezetimibe in pill form could offer a synergistic effectwith the theory that since arteriosclerosis can be caused bytogether with statins; accordingly, combination drugs were

the oxidation of LDL in the blood and its absorption into

also developed. The mechanism of action is due tofoam cells, the antioxidant effect of Probucol inhibits that

selectively inhibiting the absorption of biliary and dietaryprocess, thereby inhibiting the progress of arteriosclerosischolesterol by binding to the small intestine cholesterol(30)

transporter NPC1L1, which is responsible for cholesterol.

An early known issue with Probucol is that it reduces

absorption. This cholesterol-lowering mechanism of action is

HDL-cholesterol. Recent reports have indicated that thiscompletely different from that of ion-exchange resin.

decrease in HDL is due to increased expression of scavenger
receptor class B type I (SR-BI), a scavenger receptor
involved in the uptake of HDL, thus promoting HDL

Blood vessel

catabolism, thereby activating reverse cholesterol transport.

Liver

Use of Probucol remains low due to the fact that its

Acetyl CoA

attractive antioxidant effect has not been epidemiologically
Mevalonic acidproven and the fact that it is less effective than statins at
Cholesterol

Bile acidlowering cholesterol, despite its high dosage at 500-1,000mg
per day.

Bile acidIon-exchange resin

Ion-exchange resin
absorbing bile acid

Digestive tract

4.3.6.

Statins

Statins (named for the basic structure of the HMGCoA
reductase inhibitors) emerged as innovative new
Excretion

hyperlipidemic drugs that actually lower the cholesterol levelin the blood. They are no doubt one of the most effective

Source: Umezu 2014

drugs humans have ever developed.
Cholesterol is biosynthesized in several steps from acetyl CoA in the liver.
HMGCoA reductase is involved in mevalonic acid synthesis (1). Statins inhibit this part.
Bile acid is synthesized from cholesterol and excreted into the gut from the bile duct and thenreabsorbed (2), (3).
Resin (4) binds with bile acid and is excreted from the body (5).
Bile acid decreases, promoting its biosynthesis from cholesterol in the liver, thereby reducing
cholesterol.
Feedback acts to increase the reduced level of cholesterol in the liver, increasing the LDL receptors in
the liver (6). As a result, the LDL level in the blood decreases (7).

Lovastatin was launched in Japan in 1987 by Merck
Banyu, followed by pravastatin by Sankyo in 1989. In 2005,
Shionogi released rosuvastatin, the seventh statin on themarket. In 2011, the patent for lovastatin (Merck) expired,Fig. 4.15 Mechanisms of Action of Statins and
Ion-Exchange Resin

although out-of-patent products continued after that. The
average sales for the first statins in the decade between 2003
and 2012 was ¥238.3 billion in Japan (based on shipments:
Pharma Japan Handbook published by Jiho, various years).
The world’s highest-selling drug in 2005 was atorvastatin by
Pfizer, at $13 billion.

96

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

The Japanese drug discovery company Sankyo and its

An initial crisis emerged at this point. Despite clearing the

researcher Akira Endo (now Professor Emeritus of Tokyo

acute toxicity criteria, no change in serum cholesterol level

University of Agriculture and Technology andwas observed in young male rats after one week of dietary

Representative Director of Biopharm Research Laboratories)

administration. The control group (comparison with a groupmade significant contributions in the discovery andadministered a drug with known effects in order todevelopment of statins as medication. Several sources are

objectively observe the effect of the trial drug) was

cited in tracing the history of statin development, which wasadministered clofibrate, already in clinical use, and saw afraught with difficulties(21, 22, 23, 24).

21% reduction in cholesterol and a 32% reduction inEndo joined Sankyo in 1971 and embarked on a project

triglycerides. Since initial cholesterol-lowering in rats wasinvestigating cholesterol synthesis inhibitors. While athe global standard for assessing medicinal efficacy at the

number of methods were being used at the time in Japan andtime, this result was poorly received, both within theoverseas to treat hypercholesterolemia, including plantcompany and externally.

sterols and other cholesterol absorption inhibitors, bile acid

Endo had doubts about testing medicinal efficacy on

adsorbent ion-exchange resin and fibrates to lower

young rats with fast metabolisms; accordingly, he examined

triglyceride levels, there were no drugs with a clear

the efficacy of ML-236B in mature rats. He found thatmechanism of action that powerfully lowered cholesterol

although there was a 20-30% reduction in cholesterol within

levels.

eight hours after administration, the cholesterol level

Endo states, “At the time, the view was prevalent within

returned to its former state after that time. Discouragingly,

the company that lowering your cholesterol would put you at

supplementary administration offered no further loweringrisk, since cholesterol is a structural component of animal

effects. It was not until a little later that it was found thatcell membrane and synthesizes bile acid and steroid

inhibiting HMGCoA in rats activates a compensatory

hormones”(22). However, Endo, believing that there would

mechanism to increase the amount of enzymes (23).

be no issue if the aim was to reduce abnormal levels back to

The rat data alone was not compelling enough to makenormal levels, set the target for hydroxymethylglutaryl-CoA

Endo drop ML-236B. He sought assistance from a colleague(HMGCoA) reductase, a rate-limiting enzyme in cholesterolin another department at Sankyo, who was testing veterinary

biosynthesis. The idea was that since the majority of thedrugs on chickens and successfully convinced him tocholesterol in human blood is endogenous rather thanadminister ML-236B to female chickens that were no longer

exogenous, it is logical to prevent its synthesis there.

being experimented on and were designated to be

Endo also writes that he had an interest in mold andslaughtered. The results were surprising. The cholesterol

mushrooms since childhood and that he thought that “somelevel in female chickens administered with a diet containing

mold and mushrooms produced a cholesterol synthesis

0.2% ML-236B dropped to two-thirds within two weeks ofinhibitory substance as a means of competing against otheradministration and to one half within one month (1976).

microorganisms for survival” (22:17). Since he was using very

Female chickens require large amounts of cholesterol to

expensive radioisotopes to assess this, he devised a screening

produce eggs and have high levels of endogenous cholesterol.

system that used only small amounts and was capable ofCombined with the data from rats, it was surmised that there

screening large numbers of subjects. Using this, heare differences between species in the compensatory

conducted random screening on mold and mushroom culture

mechanism at the time cholesterol synthesis is inhibited.

filtrates. This was carried out in vitro. After screening 6,000

Statins were confirmed to have extremely potent effects,

strains in one year, he came up with a hit from a variety of

depending on species and conditions.

(Note 3)After this, ML-236B was confirmed to lower theand identify a substance known as ML-236B.

cholesterol levels in dogs as well and was used as a leadblue mold in 1973

. He refined this filtrate to isolate

ML-236B was a powerful inhibitor with inhibitory activity

compound. While medicinal chemists worked onof 0.07mg/ml in vitro. This could be used as a leadsynthesizing and refining peripheral compounds of ML-236B,

compound to synthesize analogs and obtain further candidate

no further compounds were discovered and ML-236B itself

compounds; however, it first had to be validated as being

was ultimately selected as a candidate compound for

non-toxic to mice and having a cholesterol-lowering effect indevelopment (25).

vivo.

However, a moment of tension arose at this point.
ML-236B appeared in an article published in a scientificjournal by British company Beecham as a new antibiotic(ML-236B was known as “compactin” at the time, thus
referred to hereinafter for simplicity). Fortunately, since the

Systematized Survey on the History of Drug Discovery with Technical Development

97article did not mention the compound’s cholesterol-lowering
effect, Sankyo’s utility patent had priority.

In January 1979, Endo left Sankyo to take up a

Safety testing was carried out on animals in accordance

professorship at Tokyo University of Agriculture andwith GLP standards during preclinical testing to ensure drug

Technology. The following month, having cultivated ten

safety in humans. This testing revealed a second crisis. In

strains of Monascus purpureus mold in two types of culture

1977, detailed pathological microscopy of lysosome

medium at his new laboratory, he found one of the strains toorganelles in the livers of rats administered compactin for

be producing a compactin substance. This had to be either

five weeks revealed the presence of minute crystals.

good intuition or good luck. He named the powerfully active

Discussion ensued between the group in charge of safety,

substance monacolin K and applied for a Japanese patent in

who were cautious, and the drug discovery group, who

February 1979.

favored development progress, as to whether these crystals(Note: Sankyo’s company history states that MB-530B

were beneficial or harmful, with opinions divided. The(Monacolin K) was discovered by the Institute forcompany took the side of caution and safety and suspended

Fermentation in 1974 from Monascus ruber mold as a related

the clinical application of compactin for the time being. At

compound to ML-236B. (18))

this point, compactin samples were offered to drug

However, fate works in mysterious ways. Although it hasdevelopment companies overseas to gauge their interest, but

one more methyl group than compactin, monacolin K isneither Sandoz (now Aventis), Eli Lilly nor Warner-Lambert

identical to MK-803, a substance that Merck produced at(now Pfizer) were interested, noting that it had been

almost exactly the same time from a different bacteria.

ineffective in rats.

Merck later marketed this in North American as lovastatin.

Meanwhile, Prof. Akira Yamamoto of the Osaka

Merck applied for patent in June 1979, having discovered the

University Faculty of Medicine sought to administer the drug

substance in December 1978. Endo applied for theto patients with serious familial hypercholesterolemia

monacolin K patent in February 1979.

(individuals with genetically high levels of cholesterol) andAs a result, Merck’s patent was recognized in countries

no drug remedies. In 1978, a sample was provided for aabiding by the first-to-invent system (such as the United

physician-led clinical trial, with dramatic results obtained forStates and Canada), while Endo’s patent was recognized inpatients with type IIa hyperlipidemia (heterozygous FH)

countries abiding by the first-to-file system (such as Japan,(although cholesterol levels also initially dropped

Europe and Australia). Since Endo had surrendered thesignificantly in patients with homozygous FH, there are also

patent rights for monacolin K to Sankyo, Merck could notreports of myopathy (rhabdomyolysis) occurring) (21, 22).

market its product in Japan, Europe or Australia without

Despite that the minute crystals in the rat livers wereobtaining a license from Sankyo, but records suggest thatassumed to be cholesterol ester, the safety group took a“Merck made no request to Sankyo for a transfer of license”

cautious stance and requested further long-term safety testing.

(22:68)

However, backed by the fact that a number of patients in.

In April 1980, Merck put lovastatin (MK-803, a substance

preliminary clinical trials saw actual results, full-scale phase

identical to monacolin K) to clinical trial; however, the trial

2 clinical trials were commenced in 1979. The results of thewas discontinued in September that year with the emergence

preliminary clinical trials and news of the commencement ofof information that development of compactin had beenclinical trials began to gain global attention (26).

suspended due to the results of repeated dose testing toWhen the results of the preliminary clinical trials wereindicate suspected carcinogenesis. Nevertheless, Merck

reported in May 1980 at the Eighth International Symposium

began developing lovastatin again four years later, in 1984.

on Drugs Affecting Lipid Metabolism (DALM) in Milan, theApparently, toxicity testing on animals was completed

reaction to statins was significant. However, the euphoria

satisfactorily during this interval, as well as adequate

was short-lived, as a third crisis emerged only three months

discussion and consideration on carcinogenesis, and waslater.

deemed to be of guaranteed safety.

In August 1980, during clinical trials, a98

pravastatin which went on to become a cash cow.

In the meantime, Hiroshi Mabuchi et al. of the Kanazawa

concurrently-conducted repeated toxicity test in dogs

University Faculty of Medicine published the results of a(one-year administration) found what was believed to be

preliminary clinical trial (physician-led clinical trial) on

Hodgkin’s lymphoma in the high administration group.

compactin, drawing the attention of the world again to statins.

Despite the admittedly high dosage (100 and 200mg/kg),

This probably also supported Merck’s development ofSankyo again decided to suspend development (NB:

lovastatin. In November 1986, Merck applied to the FDA for

effective dosage in humans is 1mg/kg). Later, Sankyo

approval of lovastatin. With uncharacteristic promptness, theworked on developing a back-up compactin compound,

FDA granted approval for lovastatin in September 1987.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchAccording to Shinyaku Sutachin no Hakken (Discovery of a
New Drug Statin), the New York Times published an article

Deisenhofer et al., awarded the Nobel Prize in Chemistry“for the determination of the three-dimensional structure of aon March 10 that year stating that lovastatin was a new
blockbuster drug in the treatment of cholesterol(22)

Advances have also been made in research on the bindingof statins to the active sites of HMG-CoA reductase.

. Thisprospects of statins had been predicted in US government

photosynthetic reaction centre“, reported results from X-ray
diffraction of enzyme protein and statin bonded crystals (27).

policy.
Later, Sankyo changed its development compound from

Mevalonic acid is synthesized using a substrate of
HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) and NADPH.

compactin to pravastatin, while Merck, with an eye on the
global market, also switched its main product to simvastatin

The enzyme is HMG-CoA reductase. While cholesterol isbiosynthesized after several further steps, HMG-CoA

and away from lovastatin, which was difficult to expand into
Europe and Asia without license permission from Sankyo.

reductase is the rate-limiting enzyme. Pravastatin andsimvastatin have an R-lactone ring (a) that is cleaved (b),Statins were sweeping the world market (see Fig. 4.17
Advances in Statin Research and Development).

competing with HMG-CoA in the active center of the
enzyme. Although there are two asymmetric carbons (3, 5) in

If compactin and lovastatin could be called thedawning-era first generation of statins, then pravastatin andthe mevalonic acid equivalent portion of the statins, theymust have three-dimensional structures (3-R, 5-R). Fully

simvastatin would be the second generation. Where
compactin and lovastatin are refined extracts from culture

synthetic third-generation statins (flavastatin, atorvastatin,
pitavastatin) have the butyl group portion of the second

filtrates, pravastatin and simvastatin are
strucutrally-modified, semi-synthetic extracts. Pravastatin

generation replaced by a fluorinated phenyl group to increase
the affinity. The decalin ring portion of the second

has the structure of compactin with a hydroxyl groupattached; Sankyo achieved this reaction through fermentation.

generation is also replaced by a larger hydrophobic group,
which characteristically increases the affinity to the active

prompt series of actions begs the question whether the future

Despite early difficulties in industrial-scale production due tolow productivity, large-scale mass production of pravastatin

center (Fig. 4.16) (28).
Asymmetric carbon at 3

has been made possible through a new and rare two-stage
fermentation method, in which compactin produced fromblue mold is hydroxylated using Streptomyces carbophilus, a
new species of ray fungus found in Australia (24).

Secondgeneration

Asymmetric carbon
at 5With the efficacy of statins made clear, sales began toincrease rapidly, with global drug discovery companies
entering the arena in succession. The third generation of
statins comprised synthetic products with a different parent

Decalin ring
structure
Pravastatin (acid) (R=b)
Pravastatin (lactone) (R=a)

Simvastatin (acid) (R=b)
Simvastatin (lactone) (R=a)

nucleus from the second generation. Later products were
fully synthetic, such as fluvastatin by Novartis, atorvastatin
Substituted for
fluorinated phenylgroup

by Warner-Lambert, rosuvastatin by Shionogi andpitavastatin by Nissan Chemical/Kowa. These products
demonstrated far more potent activity in in vitro testing andanimal experiments than the second generation.
While it had been validated prior to the emergence ofstatins that clofibrate and cholestyramine showed a trend of

Flavastatin (acid) (R=b)
Flavastatin (lactone) (R=a)

Atorvastatin (acid) (R=b)
Atorvastatin (lactone) (R=a)

Third generation

lowering the risk of coronary artery disease by loweringcholesterol levels, these were far from perfect in terms oflowering total cholesterol or reducing the disease onset rate
or mortality rate. Meanwhile, the combined results of fivelarge-scale clinical trials on statins, published up to 2000,
demonstrate a 25-35% reduction in LDL-cholesterol and a
20-40% reduction in the heart disease mortality rate, leaving
nobody in doubt as to the cholesterol-lowering effects of

Pitavastatin (acid) (R=b)
Pitavastatin (lactone) (R=a)

Fig. 4.16 Chemical Structures of Statins
A succession of new efficacies has been reported recently,
both in basic research and clinically. Attention is being

modern statins. The principle was found to be that inhibiting
HMG-CoA reductase to reduce the cholesterol in the liver

drawn to future research on the effect of statins on the brain

would cause an increase in LDL-receptors, causing LDL tobe absorbed into the liver from the blood, while lowering the

be connected with Alzheimer’s disease.

and their relationship with type 4 apolipoprotein, thought toMeanwhile, known side effects include rhabdomyolysis

cholesterol level in the blood (see Fig. 4.15).
Systematized Survey on the History of Drug Discovery with Technical Development99

(myopathy), which involves the breakdown and necrosis of

4.3.7.
Other Cholesterol-Lowering Medications
Research and development has progressed on othercholesterol-lowering drugs with different mechanisms ofaction. These include acetyl-coenzyme A acetyltransferase(ACAT) inhibitors and cholesterol ester transfer protein(CETP) inhibitors, aimed at increasing HDL-cholesterol, as
well as squalene synthase inhibitors, which target anotherrate-limiting enzyme that is present downstream from
HMG-CoA in the cholesterol synthesis system.

skeletal muscle cells, causing muscular pain and weakness.
In more serious cases, the high amounts of muscle protein(myoglobin) released into the bloodstream can damage theuriniferous tubules in the kidneys, causing acute renal failure.
This is not unique to statins and has been observed in fibrates
as well as new quinolone antibacterials. In 2011, the FDA
recommended the maximum 80mg dose of simvastatin only
to be used on patients who have taken the drug for 12 months
or more without myopathy.

Mention must be made of improved new drugs andfollow-on drugs. Suppose that a pioneering drug discovery
company produces an innovative new drug. Suppose alsothat there is no patent conflict and another drug discovery
company then produces a second and third drug that are
structurally similar with greater activity, fewer side effects or
are more easily administered. These are improved new drugs.
Sometimes as many as ten such drugs emerge on the market;
these are called follow-on drugs. While improved new drugs
are the characteristic forte of Japanese drug discovery
companies, they are purportedly less competent in
discovering innovative new drugs. However, when it comesto statins, both lovastatin by Merck and atorvastatin (Parke
Davis, a division of Warner-Lambert; marketed by Pfizer),
which makes more than the equivalent of ¥1 trillion in
annual sales, are improved new drugs.

While Brown and Goldstein were awarded the Nobel
Prize for their research on cholesterol metabolism, the award
was not offered to Endo. It is common knowledge that theirNobel Prize was strongly backed by the discovery of statinsand they even expressed their compliments and aspirations toEndo. Statins are among the top ten best drugs created byhumanity and attention should once more be drawn to thefact that a Japanese researcher and a Japanese drug discovery
company were very much involved in this. Fig. 4.17 shows
the advances in statin research and development to date.

From First Compound to Improved Drugs
Compactin (236B) → Pravastatin
Monacolin (lovastatin) → Simvastatin

Compactin (ML-236B)
Sankyo and Endo1973

ML-236B discovered

1974

Ineffective in rats
Patent application

1975

Patent disclosure

1976

Effective in chickens and dogs

Osaka University Faculty of Medicine
Kanazawa University Faculty of
Medicine

Consultation overseas

Overseas (Merck)

Monacolin K (MK-803 lovastatin)
Endo (TUAT)

Beecham conference presentation on
Compactin (as antibiotic only, no mention ofcholesterol)

1974 (Sankyo discovers monacolin)

No interest from major overseas companies

Jul 1976 Sample offered to Merck (noprohibited items)
Feb 1977 Preclinical trial commences
Apr 1977

Microcrystals in liver tissue

Jan 1979

Endo leaves for TUAT

1979

Clinical trial commences

Jan 1978Aug 1980 Canine acute toxicity
potential carcinogenesis

Physician-led clinical trial Dec 1978
commences in Osaka
Jun 1979
Oct 1979

Feb 1979

Monacolin discovery patented

Patent application

Sep 1979

Paper publishedMK the same substance as
Monacolin

Oct 1979

Sample offered to Merck

Nov 1979

Patent rights transferred toSankyo(Merck ‘refuses’ license consent)

May 1980

Announced atinternational conference

Apr 1980

Clinical trial commences

Sep 1981

Clinical trial results
attract attention

Aug 1980

Temporarily suspended
Toxicity testing commences

Aug 1980 Compactin discontinued in favor ofpravastatin development

1989

MK-803 discovered

Pravastatin launched (Japan)

Source: Umezu 2014

Spring 1984 Clinical trial recommenced

1986/11MK (lovastatin) FDA
application

Sep 1987

Approved

1987

Lovastatin (USA)1991

Simvastatin (Japan)
Endō A.: Shinyaku Sutachin excerpt taken from Sankyō
Haykunen-shi (100-year History of Sankyo)

Fig. 4.17 Innovative New Drugs: Advances in Statin Research and Development
Roy Vagelos, Merck’s Senior Vice-President for Research,

100

took an interest in compactin and made contact with Sankyo

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchin 1973. The discovery of lovastatin came five years later, inof some pathological processes. Centralblatt fur

December 1978 (29).

Allgemeine Pathologie und Pathologische Anatomie

Parke-Davis researchers Bruce Roth et al. started

24: 1-9 (1913) Translated in Arteriosclerosis 3:

investigating the publically-available date on copmactin in

178-182 (1983).

1982, discovering a candidate compound six years later.
However, it was found that the patent for this had already[3]

been published by Sandoz. The Parke-Davis group started

Gofman J.W., Jones H.B., Lyon T.P. et al.: Blood
lipids and human atherosclerosis. Circulation 5:

investigating again and discovered atorvastatin five years

119-134 (1952).

later, in 1993.
It must be emphasized that improved new drugs need to[4]Keys A. (Ed): Seven Countries: A multivariate

be highly evaluated. The mission is not to create drugs withanalysis of death and coronary heart disease. Harvard

new mechanisms of action, but to provide better drugs to

University Press. Cambridge, Massachusetts (1980).

humanity. Therefore, it is vital for drug discovery companies[5]

to have ways of using certain information to create better

Keys A., Taylor H.L., Blackburn H., Brozek J.,
Anderson J.T., Simonson E.: Circulation 28: 381-95

drugs faster.

(1963).

In the above example of statins, it is a fact that there are
drug discovery companies with the capabilities/mechanisms[6](systems science) to be able to create new candidate

Syed S. Mahmood, Daniel Levy, Ramachandran S.
Vasan, Thomas J. Wang: The Framingham Heartcompounds within five to six years given “certain powerful

Study and the epidemiology of cardiovascular disease:information”. This creates a significant difference between

a historical perspective. The Lancet 383: 999-1008

companies with “mechanisms and policies” and those without.

(2014).
Note 1: Following a number of trials, the American Heart[7]

Association announced in 1976 that the consumption of highFredrickson, D.S., Levy R.I., Lees R.S.: Fat transport
in lipoproteins: an integrated approach to mechanisms

amounts of butter, eggs, lard and beef was highly likely to cause
coronary heart disease. Later, the US government also announced its

and disorders. The New England Journal of Medicine

recommendation of a low-fat diet.

276 (1): 34-42 (1967).
[8]

Note 2: The Japan EPA Lipid Intervention Study (JELIS) was

The Lipid Research Clinics Coronary Primaryconducted on 18,645 Japanese hyperlipidemia patients (14,981

Prevention Trial: Results I. Reduction in incidence ofcoronary heart disease primary prevention patients and 3,664

coronary heart disease. Journal of American Medicalsecondary prevention patients). This was the world’s first

Association 251 (3): 351-64 (1984).

prospective randomized open-label trial, tracking the cumulative
incidence of major coronary events in an EPA+statin administrationgroup and a statin-only, EPA-non-administration group for five

[9]

Bruckert E., Labreuche J., Amarenco P.: Metaanalysisof the effect of nicotinic Acid alone or in combination

years (4.6 years on average). There were 324 instances (3.5%) ofmajor coronary artery disease in the control group and 262 instances

on cardiovascular events and atherosclerosis.

(2.8%) in the administration group.

Atherosclerosis 210 (2): 353-361 (2010).

Note 3: Details on the drug discovery screening process are given in[10] Kōwa Hyakunen-shi (100-year History of Kowa).
Kowa Company, Ltd. 373-374 (1994).

Chapter 3: Technological Advancement of Pharmaceutical Drug
Discovery.

[11] Studer M. et al.: Effect of different antilipidemic agentsand diets on mortality: a systematic review. Archivesof Internal Medicine 165: 725-7 (2005).

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Cholesterol and Controversy: Past, Present andFuture: Scientific American By Jeanne Garbarino,

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November 15, (2011)948-949 (1962).

http://blogs.scientiﬁcamerican.com/guest-blog/2011/11[2][13] Blumcke S., Schwartzkogff W., Lobeck H.,/15.

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[25] Endo A., Kuroda M., Tsujita Y.: ML-236A, ML-236B,

D., Wiegand H.J.: Hepatic peroxisome proliferation inand ML-236C, new inhibitors of cholesterogenesis

rodents and its significance for humans. Food andproduced by Penicillium citrinum. Journal ofChemical Toxicology 31: 857-907 (1993).

Antibiotics 29: 1346-1348 (1976).

[15] Martin G., Schoonjans K., Lefebvre A., Staels B.,
Auwerx J.: Coordinate regulation of the expression of[26] Yamamoto A., Sudo H., Endo A.: Therapeutic effectsof ML-236B in primary hypercholesterolemia.

the fatty acid transporter protein (FATP) and acyl

Atherosclerosis 35: 259-266 (1980).

CoA synthetase (ACS) genes by PPARα and PPARγ[27] Istvan Eva S., Johann Deisenhofer: Structuralactivators. Journal of Biological Chemistry 272:
28210-28217 (1997).
[16] Schoonjans K., Watanabe M., Suzuki H. et al.
Induction of the acyl-coenzyme A synthetase gene byfibrates and fatty acids is mediated by a peroxisome
proliferator response element in the C promoter.
Journal of Biological Chemistry 270: 19269-19276(1995).
[17] Yoshitomi Seiyaku Gojūnen no Ayumi (50-year History
of Yoshitomi Pharmaceutical Industries). Yoshitomi

mechanism for statin inhibition of HMG-CoA
reductase. Science 292: 1160-1164 (2001).
[28] Vaughan Carl J., Antonio M. et al.: Update on Statins.
Circulation 110: 886-892 (2004).
[29] Shook R. (orig. auth.), Kobayashi R. (trans.): Shinyaku
Tanjō (Miracle Medicines). Diamond (2008).
[30] Iyakuhin Intabyū Fōmu (Drug interview form).
Probucol. Otsuka Pharmaceutical (2013) (13threvision).
[31] Details of other pharmaceutical products taken fromdrug interview forms and package inserts.

Pharmaceutical Industries, Ltd. 172-173 (1990).
[18] Kawamatsu Y., Asakawa H., Saraie T., Imamiya E.,
Nishikawa K., Hamuro Y.: Studies on

4.4 Drugs that Act on the Blood Systemantihyperlipidemic agents. II Synthesis and biologicalactivities of 2-chloro-3-arylpropionic acids.
Arzneimittelforschung 30: 585-589 (1980).
[19] Sohda T., Mizuno K., Imamiya E., Sugiyama Y.,
Fujita T., Kawamatsu Y.: Studies on antidiabetic
agents. II: Synthesis of
5-(4(1-methylcyclohexylmethoxy)-benzyl)
thiazolidine-2,4-dione (ADD-3878) and its derivatives.
Chem Pharm Bull (Tokyo) 30: 3580-3600 (1982).
[20] Alexander Tenenbaum et. al: Peroxisome
Proliferator-Activated Receptor Ligand Bezafibrate
for Prevention of Type 2 Diabetes Mellitus in Patients
With Coronary Artery Disease. Circulation 109:2197-2202 (2004).
[21] Yamauchi K.: Sekai de Ichiban Ureteiru Kusuri (TheMost Popular Medicine in the World). Shogakukan 140(2007).
[22] Endō A.: Shinykau Sutachin no Hakken (Discovery ofa New Drug Statin). Iwanami Shoten (2006).
[23] Tsukasaki A.: Shinyaku ni Idonda Nihonjin (Japanese
Scientists who Strived for New Medicine). Blue Backs.
Kodansha (2013).
[24] Sankyō Hyakunenshi (100-year History of Sankyo).

102

This section provides an overview of drugs used to treat
clots, hemorrhages and other cardiovascular abnormalities
that interfere with the natural activity of the blood, causing
serious functional impairment.
Thrombotic disorders caused by coagulation of blood that
normally flows within the blood vessels include acute
myocardial infarction, deep vein thrombosis, pulmonary
embolism and acute ischemic stroke. These disorders aretreated using anticoagulants and thrombolytics. According to
the 2008 Patient Survey Overview by the Ministry of Health,Labour and Welfare, the total number of patients receiving
ongoing treatment for ischemic heart disease was 810,000,
while the total number of patients receiving ongoingtreatment for strokes, including cerebral infarction andcerebral hemorrhage, was 1.34 million. These figures are
predicted to continue to increase as ageing society advances.
Increasing incidences of thrombosis and pulmonary
embolism have gained attention in recent years, along withthe term “economy class syndrome” or “long flight
syndrome”.
While hemorrhagic disorders can be hereditary, such as
hemophilia, or occur pathologically, such as postoperative
fibrinolysis, hemorrhaging can also occur after using
anticoagulants.
Currently, there are relatively few patients withhemorrhagic disorders compared to those with thrombolytic

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchor embolic disorders, but it goes without saying thatpreventing hemorrhage is crucial to preserving life.

Intrinsic system

Hematological drugs can be classified as (i) antiplatelets,(ii) anticoagulants, (iii) thrombolytics and (iv) hemostatics.
Extrinsic
systemThrombosis is mainly caused by the generation of fibrins
with the stimulation of the blood coagulation system
resulting from vascular wall damage due to arteriosclerosis,changes in blood components or abnormal blood flow, as

Factor IIa

well as the formation of platelet aggregates, resulting inProthrombin

vascular stenosis (narrowing of blood vessels, making it

Thrombin

Factor II

difficult for blood to pass through) or occlusion (blood vessel
blockage).

Fibrinogen

FibrinThrombus formation is mainly due to the coagulation

FibrinMonomersystem and the platelets involved in fibrin production.
Platelet and the coagulation cascade work together in the
body to cause the blood to clot. When a blood vessel isdamaged, platelets first adhere to the vascular endothelium

Polymer

Numerals indicated in boxes represent enzyme names. XII is an abbreviation
for Factor 12; XIIa refers to activated Factor 12 (a stands for activated). X(Factor 10) is activated in both intrinsic and extrinsic cascade pathways; theactivated factor Xa converts prothrombin into thrombin. Thrombin acts to form
fibrinogen into fibrins.
This diagram is abridged; there are more complex controls and activation
mechanisms and factors at work in the cascade.

and then aggregate together to form a primary hemostatic
plug around the opening of the wound. After that, various

Fig. 4.18. Blood Coagulation Cascadeclotting factors are released to coagulate the fibrins in the
blood, forming a secondary hemostatic plug.
Fibrin coagulation is a continuous reaction that takes placeby means of the mechanism shown in Fig. 4.18. This is- An antithrombin formulation (Behring) was developed
and marketed in Japan by Hoechst Japan in 1987. An

called the blood coagulation cascade. The intrinsic
coagulation pathway and the extrinsic coagulation pathway
are both transmitted through several continuous chain

activated protein C formulation was also released as ahematological drug in 2000. The fibrins that are produced are broken down in thereactions involving the gradual conversion from plasma
factors (enzyme precursors) to activated enzymes (mainly
serine proteases). (This cascade has 12 types of coagulation
factors, which have been numbered by Roman numerals inorder of discovery.) The final step in the cascade involves
activated Factor Xa (FXa), an enzyme that converts

fibrinolytic (fibrinolysis) system. The key component in thissystem is plasmin. Plasminogen is present in the blood as aprecursor; it breaks down fibrin clots after being converted
into the active enzyme plasmin by the action of tissue
plasminogen activator (t-PA). The blood in the body iscontrolled by the balance between the coagulation andprothrombin into thrombin, and activated Factor V.
Thrombin activated by the enzyme action of FXa acts on the

fibrinolytic systems (see Figure 4.19).

mesh-shaped fibrin precursor fibrinogen to produce fibrin
monomers; these fibrin monomers link together throughWarfarin

covalent bonds to form fibrin polymers. Finally, the enzyme

Tissue plasminogen activator

action of FXIIIa forms a stable fibrin clot and coagulation is
Coagulation
systemcomplete. Thrombin is activated Factor II.

Thrombus
EmbolusThe body also has mechanisms to prevent excessive
Platelets

stimulation of the coagulation system. One mechanism isantithrombin (AT), which controls excessive thrombus

Aspirinformation by binding to thrombin, FXa and FIXa to inhibit
their action, thereby localizing coagulation. Anothermechanism is the thrombomodulin (TM) and protein C

Fibrinolysis

 Formation of thrombi/emboli
prevented by aspirin/warfarin
 Thrombi/emboli that form arebroken down by t-PA
 Many new
anticoagulants/antiplatelets havebeen created by Japanesecompanies.

Fig. 4.19 Coagulation/Fibrinolysis System and Drugs

control system. TM binds with thrombin to convert theprotein C in the blood into activated protein C (APC). APC
breaks down VIIIa and Va in the coagulation system, thus
avoiding the generation of fibrins and controlling thrombus
formation.

Platelets are blood cells that are fragments ofmegakaryocyte cytoplasm protrusions. They are amorphousin shape and have no nucleus. The platelet membrane has
receptors that bind to thrombin, serotonin (5HT), ADP and

Systematized Survey on the History of Drug Discovery with Technical Development

103

exposed collagen. In the absence of damage to a blood vessel,

Takashi Hayashi) and Mitsubishi Chemical in 1947, whenplatelets circulate freely in the blood in a regulated state.

battle scars were still fresh from the war. Okamoto was at

When the receptors are activated by attaching to ligands,

that time working at the Keio University Faculty Medicine as

granules within the platelet cells are released into the blood;

the Hayashi Kenkyusho representative, while Fujio

the ADP, serotonin and other substances within these

Nagasawa, the institute’s deputy director and representative

granules act on the receptors on other platelets, causing afrom Mitsubishi Chemical, was in charge of planning andreaction chain phenomenon. The platelets interact with eachother, resulting in aggregation (primary hemostatic plug)
2)

(Note

. The activated platelets also activate the coagulation

direction. Research began in 1947 at the Mitsubishi
Chemical laboratory at Mizonokuchi in Kawasaki.
According to Sekai wo Ugokasu Nihon no Kusuri

system, triggering the polymerization of fibrins to form clots(Japanese Medicine to Move the World) (Okamoto S. (ed.),(secondary hemostatic plug).

Tsukiji Shokan, 2001) (3), this concept of a joint laboratory

Although the number of cerebral infarction andwas unique. The concept was to “firstly, delineate

myocardial infarction patients has grown recently, attention

international standards, secondly, to target fields that wereis now being given to secondary prevention following thestill untouched and unexplored by researchers, and thirdly, toacute phase. There are growing hopes for anticoagulants andproduce drugs that were useful in the treatment of diseases”.

antiplatelets to achieve this. An increase in pulmonary

While the postwar drug production industry wasthromboembolism and deep vein thrombosis, known as longconcentrating on sulfa drugs, penicillin and other antibiotics

flight syndrome or economy class syndrome, has also been

and antihistamines, the research question selected by thisnoted. Even in everyday life, modern humans are suffering

project was antiplasmins, a highly original field with nofrom disorders caused by coagulation or clotting of the blood.

competition anywhere in the world.

While basic research has long been carried out on theIt has long been known that there are specific enzymes

coagulation system, there has been a rapid increase in recent

that break down fibrins in the blood. Oxford University

years of basic research on the mechanisms leading fromresearchers Robert Macfarlane and Rosemary Biggs

platelet receptors to aggregation, with successive drugs

discovered a protease that rapidly and selectively broke

emerging to inhibit various different parts of the signal

down fibrins in the blood, naming it plasmin soontransduction pathway leading to thrombosis(1, 2).

afterwards.

In the area of hemostatics, Japanese universities andOkamoto wrote, “For screening, the in vitro system was

private companies collaborated in a modern drug discovery

selected, allowing highly efficient experimentation without

approach to produce the world’s first low-molecular-weightusing animals. A fibrin solution was created in a test tube,

hemostatic drug at a time when drug discovery systems werewhile equine plasma was treated with low acidity to produce

far from complete, still suffering the effects of the Second

a precipitate containing plasmin. This was added to the fibrin

World War. The following section outlines some of thesesolution and the decomposition rate measured. Available

drugs.

compounds were sequentially screened. Negatively-charged
glutamic acid and aspartic acid appeared to promote the4.4.1.

Hemostatics

Natural extract protamine sulfate (extracted from thepositively-charged arginine and histidine appeared to inhibit

testes and semen of fish; it is positively charged due to its

the action of the plasmin; thus, the focus fell on lysine, anhigh arginine content; used to antagonize the anticoagulantamino acid that is similarly positively charged. However, it

effect of heparin) has been used to neutralize the effects of

was almost impossible to obtain amino acids such as lysine

heparin(Note 3)in patients undergoing anticoagulation therapy.

While vitamin K as well as aprotinin (a bovine lung protein

104

action of the plasmin, albeit slightly, whilein that postwar period” (3:14).
They were eventually able to obtain lysine and examine itsthat has a serine protease catabolic enzyme inhibitory effectactivity to confirm its powerful effect. Not long afterand inhibits plasmin) have also been used to prevent bleeding,

discovering the inhibitory activity of lysine, the focus fell on

low-molecular-weight synthetic drugs emerged in the 1950s

nylon as a lysine analog. Nylon stockings were hydrolyzed inand 1960s, including aminocaproic acid and tranexamic acid.

hydrochloric acid to produce needle crystals. When these

Noteworthy in the history of Japanese drug discovery,

were tested, they were found to have an even more powerfulthese synthetic hemostatics were researched and developed

inhibitory activity than lysine. Thus, the antiplasmin epsilon

independently in Japan. Although they were discovered by a(ε-aminocaproic acid) came into being. While lysine has ateam working under Prof. Shosuke Okamoto of the Kobe

caproic acid structure with amino groups in the alpha andUniversity School of Medicine, joint research began between

epsilon positions, epsilon has no amino group at the alphaHayashi Kenkyusho (a private institute founded by writerposition; it was found to have an antiplasmin effect around

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchten times more powerful than that of lysine. Althoughepsilon has been considered possible to implement clinically
due to its low toxicity, its clinical application has been
non-committal as there is no precedent concept for such aTranexamic aciddrug.
Around this time, it started becoming known that plasminincreases in the event of allergy or functional uterine
bleeding. Clinical trials were conducted by the Departmentsof Pediatrics and Obstetrics & Gynecology at Keio
University; the results were confirmed for chronic allergic
eczema in children and for functional uterine bleeding.

Fig. 4.20 World-First Synthetic Hemostatics

Full-scale clinical testing was undertaken by Daiichi
Pharmaceutical (4:81-85).
At the time, pharmaceutical product approval in Japan
mainly related to safety. This was a time when dozens andThere is much to be learnt from the attitude of drug

even hundreds of patients were approved if they did notpresent with side effects. The United States Patent anddiscovery companies in the difficult postwar era,
successfully undertaking industry-academy collaborative

Trademark Office even has a record stating that when an
application was made for an American patent for epsilon inprojects and setting targets irrespective of current trends,
with high aims of discovering drugs worthy of evaluation at

the 1950s, “a complete review was called for, as there wasinsufficient data on the medicinal efficacy; the project team,international level. “Target exploration” in the age of 21st
century genomic drug discovery has incorporated the idea of

which comprised a number of physicians from various
departments of the Keio University School of Medicine,first creating a target enzyme or receptor inhibitor and thenconsidering the applicable diseases for treatment (seeresponded with their results” (3:19-21).
Although the hypothesis that the inhibition of plasmin

Chapter 3), although, surprisingly, a similar idea has alreadyexisted in Japan for over 68 years. Optical resolution ofwould be therapeutic was proven, epsilon lacked sufficient
medicinal efficacy to be able to treat plasmin-related severe

active substances is also being carried out in this era.
These hemostatics were launched on the market bybleeding events or serious bleeding such as that
accompanying lung surgery. Accordingly, efforts continued

Daiichi Pharmaceutical. In 1969, approval was given for an
additional indication for allergic inflammation. Sales are saidin order to further increase its activity.
Epsilon has a simple structure with five carbon atoms andto have peaked at ¥4 billion (4:130, 5). With drug production
volumes in Japan at around ¥450 billion in 1965, it is clear

a five-ångström hydrocarbon with positive and negative
charges at each end. Several compounds were synthesizedthat epsilon and tranexamic acid were significant discoveriesboth for academia and for business.

replacing the straight-chain hydrocarbon with a cyclichydrocarbon to make this distance fixed; one such compound
was aminomethyl cyclohexanecarboxylic acid (tranexamicacid). Tranexamic acid is a stereoisomer; it was successfully

4.4.2.
Anticoagulants
Bleeding and clotting are opposites, but it is essential forthe body to have a balance between the two. Okamoto shiftedbroken down by Masashi Shimizu et al. of Daiichi
Pharmaceutical, no simple task for the time (3:25). The result

focus to the discovery of anticoagulants (mentioned later). In
the 1970s, lifestyle-related diseases were rare in Japan andwas powerful efficacy for the chair-type (trans-) isomer andhardly any activity for the board-type (cis-) isomer. Thus

thrombosis was not as problematic as it was in the West.
Instead, hemorrhagic disorders were the focus of attention.

created, tranexamic acid was ten times more potent thanepsilon.

However, as eating habits and lifestyles changed to a more
Western style with the rapid growth of the economy, theEpsilon-aminocaproic acid was released on the market in
1954, followed by tranexamic acid in 1965. These are still

number of thrombosis patients also increased and Japanbegan initiatives to combat thrombosis.

widely used today as oral drugs and injected drugs, not onlyin Japan, but internationally as well. The 2012 edition of the

Meanwhile, in the West, there were a number of studies
being conducted in the 1970s on the treatment of thrombosis.

American textbook Pharmacology in the Lippincott
Illustrated Review Series states that “fibrinolysis can be

While this research laid the foundation for heparin treatment
and warfarin treatment to regulate the blood coagulation

controlled by the administration of ε-aminocaproic acid ortranexamic acid. Both products are synthetic compounds, arecascade and fibrinolytic treatment to break down clots, each
had their own problem areas. The following is an outline ofeffective when administered orally, are excreted in the urine
and inhibit the activation of plasminogen” (1) (see Fig. 4.20).

this history, with details of anticoagulant drug discovery
begun in Japan.

Systematized Survey on the History of Drug Discovery with Technical Development

105Heparindeveloped, with approval limited to preventing coagulation

The history of anticoagulants began with the discovery of
the anticoagulant effect of heparin by medical student Jay

during hemodialysis. All of the other drugs were imported
from overseas, with very little domestic research in Japan (18).

McLean in 1916 using canine liver.
Heparin is a mixture of linear acidic mucopolysaccharides

Warfarin

made up of repeating units of uronic acid and glucosamine,

Warfarin comes from a coumarin compound isolated fromalso present in human cells. Heparin molecules contain adecomposed sweet clover by Karl Paul Gerhard Link et al. ofhigh amount of sulfate groups and are negatively charged.

the University of Wisconsin as part of a causal investigation

Heparin from porcine intestinal mucosa has long been used

on a phenomenon occurring on ranches in the United States

as a treatment drug.

and Canada in the 1920s, in which cattle that had eaten

Heparin binds with heparin cofactor (antithrombin III
4)

(Note

decomposing sweet clover were bleeding to death. This

) and changes its structure to increase the efficacy ofcompound was found to be the cause of the hemorrhagic

antithrombin III one thousand fold. Antithrombin III binds

disorder. An analog, dicumerol, was synthesized and used aswith thrombin, FXa (activated Factor X) and serine proteasea rodenticide. While dicumerol was later even used clinically(a protease with serine at the active center; many enzymes inas an anticoagulant, a later derivative, wafarin, offered betterthe coagulation cascade are of this type) active sites to inhibit

gastrointestinal absorption and an application was made to

the action of those enzymes. In other words, antithrombin III

patent it as a coagulation inhibitor in 1945. Its efficacy wasregulates the coagulation cascade. Heparin binds withvalidated and it began to be used as well as heparin as anantithrombin III and changes its structure to enhance its

anticoagulant in the United States in the 1950s.

inhibitory effect.
Heparin was developed as a pharmaceutical product inBiosynthesis of blood coagulation factors prothrombin(Factor II), Factor VII, Factor IX and Factor X occurs in the

Canada (1937) and in Sweden (1939). In Japan, sodium salt

liver. This involves vitamin K as a coenzyme to thesebegan to be marketed in 1962 as a treatment and preventionamino-terminal converting enzymes. Research has shown

for arterial/venous thrombosis.

that warfarin acts to antagonize vitamin K and inhibit the

Heparin has long been used clinically as an injected drug;

biosynthesis of these enzymes, as well as indirectly

however, side effects have included: (i) the possibility of

inhibiting blood coagulation. As mentioned previously,

antigenicity, since it is produced by non-human animals

prothrombin is a vitamin K dependent factor that is(processed from bovine or porcine intestinal mucosa, with aparticularly important in the blood coagulation cascade.

molecular weight range of around 30,000 to 35,000, it is not

Where other coagulation factors have short half-lives of 6-36

a single substance) and (ii) hemorrhagic complications

hours, prothrombin has a long half-life of 60-72 hours.

despite the original effect. Other side effects observed

Warfarin is thought to demonstrate its anticoagulation effectincluded (iii) thrombocytopenia and (iv) thrombosis. Whilemainly by reducing the levels of prothrombin due to it being

caution was necessary because of these side effects, bleeding

unable to biosynthesize. Consequently, it can take 3-4 days

was a particularly major drawback. Since the action of

from administration for the effects of the drug to manifest;

heparin was significantly affected by the amount of

conversely, the effects can continue for 4-5 days after

antithrombin III, there were also issues with the level of side

administration has been ceased.

effects differing between individual patients.

Warfarin has become widely used around the world due toWith the aim of reducing these side effects,

its low cost and reliable antithrombotic effect. However, like

low-molecular-weight heparin (LMWH), with a molecularheparin, warfarin has long had issues with its

weight of 6,000 or below, was produced from unfractionateduser-friendliness, as the optimal dosage varies between

heparin by enzymatic and chemical depolymerization.

individuals. Even though it is the best drug in use today, its

LMWH did not require such focused monitoring as heparin

blood concentration levels still require monitoring.

and began to replace heparin in clinical application. However,
little difference was observed in side effects other thanthrombocytopenia. In Japan, dalteparin sodium (approved in106

Antithrombotics: Argatroban
Prof. Shosuke Okamoto (mentioned previously) examined1992), parnaparin sodium (approved in 1994), reviparin

the available information on antithrombotics in the West at

sodium (approved in 1999) and other similar drugs were

the time and wrote that “given the circumstances, there

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchSince ℓ-arginine is characterized by a having basic

should be several antithrombotic substances or otherthrombotic treatments prepared for clinical use”
Thrombin was selected as the target for this

(3:38)(Note 5)

guanidino group, it was assumed that this could be.

. Researchcommenced in 1970 with the hypothesis that while plasmincounteracted by aspartic acid, which has a highly-acidic
carboxyl group at the enzyme site (see (i)) (specific pocket).
Amino groups, imino groups and guanidino groups withcleaves the C-terminal region of the amino acid lysine,
thrombin cleaves the C-terminal region of arginine, meaningthat there should be inhibitors in the periphery of arginine.

organic bases to counteract the aspartic acid residue at (i)were investigated, with the guanidine group eventuating as
the best. Site (ii) of the tripod structure was envisaged as a

Unfortunately, no candidate compounds were discovered inhydrophobic substituent pocket. Since the ninth position

the periphery of arginine; however, extended screening

from the N-terminus of the A chain of fibrinogen hydrolyzed

resulted in the discovery of low-level activity byby thrombin is always phenylalanine in mammals of all

tosylarginine methyl ester (TAME), a quantity reagent for

species, an aromatic hydrophobic amino acid residue isthrombin activity. This was selected as a lead compound.

present near the active center, which is thought to play an

Okamoto again collaborated with Mitsubishi Chemical toimportant role in substrate specificity. Thus, an aromatic

draw from the company’s success with hemostatics. A

hydrophobic substituent was selected (aromatic binding

research team was established in Mitsubishi Chemical’s

pocket). (iii) is the region corresponding to the C-terminus ofpharmaceuticals department, led by synthetic organic

arginine; the wall on the enzyme side is presumed to have achemist Ryoji Kikumoto. Kikumoto demonstrated his worth

narrow slit-shaped hydrophobic structure (hydrophobic slit).

as a medicinal chemist on this project, producing a

Based on this hypothesis, synthesis was undertaken

thrombin-specific inhibitor. Based on the information

systematically to produce one pocket and then the others byavailable in 1970, Kikumoto proposed a molecular designchanging the group for each pocket. Upon examination of theconcept for the project. This comprised a tripod structure,

structure-activity relationship, the optimum specific pocketwith the idea that thrombin has three pockets (see Fig. 4.21).

for (i) was found to have a length of 4-5 carbons, while the4-methylpiperidine was found to be optimum for (ii). With
these established, (iii) was modified, with in vitro analysis

Aspartic acid

Argatroban

showing a gradual increase in inhibitory activity compared to
the lead compound TAME. No. 205 showed I50(i) Specific pocket
Guanidine group(representing the concentration at which the coagulation time
doubled using the thrombin activity evaluation method; thelower the value, the more powerful the effect) that was
10,000 times more powerful than TAME.
Examination of inhibitory action on serine proteases otherAromatic ring (R1)

Aliphatic (R2)

than thrombin revealed very high thrombin specificity,
indicating that this was a thrombin-specific inhibitor. No.

(ii) Aromatic binding pocket

205 was presumed to bind to thrombin active sites at the(iii) Hydrophobic slit

third point on the conjectured tripod. The tripod hypothesis
turned out to be correct (6) (see Table 4.4 Argatoban Enzyme

Fig. 4.21 Tripod Hypothesis

Selectivity).

Thrombin selectively cleaves the C-terminal region of

Table 4.4 Argatoban Enzyme Selectivity

arginine. In other words, it causes limited proteolysis of the

EnzymeKi (μM)

arginine-glycine bonds between Aα chains 16-17, Bβ chains

Thrombin

0.039

FXa

210

14-15 and Factor XIII 36-37 in the fibrinogen substrate. Thismeans that there are areas with confirmed arginine residue

Plasmin800

Kallikrein

1,500with specific C-terminal and N-terminal structures near

Trypsin

5.0

thrombin active sites.

t-PA

210

U-PA

>1,700Further, since ℓ-arginine enters thrombin active sites,
lysine and d-arginine demonstrated no inhibitory effect.

Argatroban had high selectivity for thrombin.

Systematized Survey on the History of Drug Discovery with Technical Development

107However, experiments on rats showed this compound tohave high acute toxicity. A number other compounds weresynthesized to avoid this. One of these compounds, No. 407,
was obtained by introducing a carboxyl group to the
C-terminus, reducing the acute toxicity to one-tenth that of
No. 205. Kikumoto conjectured that “these compounds are
thrombin-specific, with the exception that they have very
high affinity to pseudocholinesterase. Introducing thecarboxyl group would make No. 407 lose its
pseudocholinesterase inhibitory effect, which would be thekey point of reducing the acute toxicity.”
To optimize the compound further, the (R1) structure
affinity at (ii) was modified to produce the final compound.
This was the 700th compound to be synthesized since TAME;
it was a 4-methylpipecolin-2-carboxylic acid with four
isomers. Kikumoto conjectured that, of the four isomers, 2R
and 4R would demonstrate the strongest activity, and hedeveloped a new synthetic method of
4R-methylpipecolin-2R-carboxylic acid: four stereoisomers
were split, with isomers synthesized for each of them. This
resulted in a surprisingly significant difference between thestrongest (2R, 4R) isomer and the weakest (2S, 4S) isomer,
with the strongest being 15,000 times more powerful than theweakest. The 2R, 4R isomer became the pharmaceuticalproduct argatroban (No. 805) (7) (see Figures 4.22 and 4.23).

(i.p. mouse)(i.p. mouse)argatroban(i.p. mouse)

Fig. 4.22 Antithrombotic Optimization

108

Fig. 4.23 Schematic Diagram of Argatroban
Enantiomer Binding to Thrombin Active Site
The laboratory later conducted X-ray analysis on anargatroban-thrombin complex to clarify the structure of thebinding site in detail. It was the same as the relationshipbetween argatroban and the active center hypothesized by
Kikumoto in the exploratory research.
Developing No. 805 as an antithrombotic required
validating its efficacy in animal experiments. Yoshikuni
Tamao et al., in charge of pharmacology, came up with a
new model involving exposing the carotid artery of a rabbit
and immersing the outside of it in acetic acid. The acetic acid
penetrated into the arterial intima cells, damaging thevascular endothelium and causing a blood clot within 2-3
hours. Viewing under scanning electron microscopy revealed
that the clot was a platelet thrombus. The opinion at the time
was that antiplatelets such as aspirin were effective against
platelet thrombi, while anticoagulants such as heparin andwarfarin were not; this study drew the same conclusion.
However, argatroban administered by intravenous injection
demonstrated a powerful efficacy; unlike heparin, which
worked its effect through antithrombin III, this drug was
found to work its antithrombotic effect by directly inhibiting
thrombin, showing great promise for clinical application (8).
As well as suppressing fibrin production by inhibiting
thrombin, argatroban also inhibited the fibrin stabilizing
effect of Factor XIII and demonstrated a platelet aggregation
inhibitory effect.
The key players of the 1970s were the medicinal chemists.
The history of argatroban research is a typical example oftheir experience and intuition being put to use in clarifying
structure-activity relationships in drug discovery. Based on
the initial hypothesis, more than 800 compounds wereorganically synthesized and tested by trial and error until atarget was reached. This commendable approach resulted in
the release of the world’s first thrombin inhibitor onto themarket. However, argatroban does not readily dissolve inwater, making oral administration difficult. The drug waslaunched in 1990 as an injected drug indicated for chronicarterial occlusion. In 2000, it was approved forheparin-induced thrombocytopenia (HIT) in the UnitedStates. Approval was granted in Japan for the same
application in 2008.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchLater, antithrombin antagonistic FXa inhibitor

While it has long been known that certain types of snake

fondaparinux appeared as an injected drug in 2007. While

venom contain substances that affect blood clotting, it was

researched and developed by Sanofi Sante, clinicalnot until 1960 that Pentapharm (Switzerland) isolated adevelopment in Japan was consigned to GSK. Since this drug

thrombin-like enzyme from the venom of the common

enabled greater antithrombin III FXa inhibiting selectivity, it

lance-head pit viper Bothrops atrox, found in a wide-ranging

was used in the prevention and treatment of venous

habitat throughout Central and South America. A

thromboembloism (VTE). The emergence of fondaparinux

comparative examination of snake venoms found this venom

also proved that even with poor thrombin inhibition,

to contain a protein that lowers the fibrinogen levels in thethrombosis could be prevented and treated by inhibiting FXa

blood. This substance, known as batroxobin, was clinicallyfurther upstream in the coagulation cascade.

confirmed to have a fibrinogen-lowering effect and wasapproved for use on thrombotic diseases in many countries.

Oral Anticoagulants

In Japan, Tobishi Seiyaku noted a peripheral circulation

With long-term administration of injected drugs proving

improving effect and developed this, gaining approval inproblematic to patients, companies began to compete over1993 to use this as an antithrombotic peripheral circulation

the research and development of orally-administeredimprovement agent.

antithrombotics and FXa inhibitors. As explained by theThrombomodulin alpha (TM-α), developed by Asahi

structure-activity relationship of argatroban, the idea was toKasei Pharma in collaboration with Prof. Maruyama of

inhibit thrombin and FXa by the entry of a guanidino group

Kagoshima University and Prof. Suzuki et al. of Mie

into the active center; however, it was found that the

University using gene recombination technology, is theguanidino group also caused a decline in absorption by theworld’s first human thrombomodulin. It was released on thebody.

market in 2008 as an injected drug indicated for disseminatedintravascular coagulation (DIC) (Note 6).

Consequently, new compounds emerged with pyridine

Thrombomodulin is a glycoprotein present on the surface

rings and with chlorothiophene structures in place ofarginine-analogous structures. In 2011, Nippon Boehringerof vascular endothelial cells that demonstrates an

Ingelheim launched the oral antithrombotic daibigatran,

anticoagulation effect by forms a complex with thrombin in

indicated for “inhibiting the onset of ischemic stroke andthe blood. It has the effect of suppressing abnormal thrombin

systemic embolism in patients with non-valvular atrial

activation. While injecting this could be expected to have an

fibrillation”. The same year, Sankyo released Japan’s first

anticoagulation effect, natural thrombomodulin is aoral FXa inhibitor edoxaban, indicated for “inhibiting themembrane protein that is present on the vascular endothelial

onset of venous thromboembolism (VTE) in patients

cells and is insoluble. Since it is preferable forundergoing or having undergone orthopedic surgery on thepharmaceutical products to be soluble, researchers at Asahi

lower limbs”. In 2012, FXa inhibiting rivaroxaban (Bayer)

Kasei Pharma used biotechnology to successfully convert thewas released on the market with similar indications.

extracellular section containing the thrombomodulin active

Apixaban is an orally-administered anticoagulant jointly

sites into soluble molecules, thus developing

developed by Bristol-Myers Squibb (BMS) and Pfizer tothrombomodulin-α, or recombinant human soluble

reversibly inhibit FXa. This drug was approved and marketed

thrombomodulin (rsTM). rsTM is the world’s first drug to be

in Japan in 2013 for its efficacy in “inhibiting the onset of

more effective than heparin, used in a prospective

ischemic stroke and systemic embolism in patients withcomparative clinical study on DIC patients. rsTM was

non-valvular atrial fibrillation”. A recently publishedproven to inhibit the onset of DIC by promoting themeta-analysis of comparative studies between warfarin andactivation of protein C to prevent the activation of thrombin;these oral anticoagulants showed them to be significantly

it was also proven to have a lower hemorrhagic effect thanbetter in terms of the relative risk of intracranial hemorrhage

heparin (11).

(9). With this side effect having been deemed to be ofparticular concern to Asians, who are more susceptible to4.4.3.
Platelet Aggregation Inhibitors
Platelet aggregation is suppressed by aspirin. While

intracranial hemorrhage, these oral anticoagulants are
expected to reduce that risk.
There is also ongoing focus on the efficacy of these neworal anticoagulants in preventing cerebral hemorrhage inaspirin was originally used as an anti-inflammatory for its
antipyretic and analgesic effects, since the discovery by H. J.

patients with atrial fibrillation (10).

Weiss et al. in 1967 that aspirin at low doses had a platelet
aggregation inhibitory effect (12), multiple large-scale clinical

Macromolecular Anticoagulants

studies have proven the utility of aspirin as an antiplatelet
drug. In 1998, all aspirin formulations (non-prescription

Systematized Survey on the History of Drug Discovery with Technical Development

109

drugs) were confirmed by the FDA for suppressing
thromboembolism in atherosclerotic diseases. Aspirin is now

antithrombotic effect”, this became more complicated withother opinions that “inhibiting platelet aggregation canused as an antiplatelet drug in countries all over the world. In
Japan, enteric coated aspirin tablets have been marketed byprevent thrombi from forming but cannot break down
existing thrombi” and that “it makes sense to prevent theBayer as antiplatelet drugs since 2001, indicated forsuppressing thromboembolism in myocardial infarction andformation of new thrombi, since there must be some kind ofthrombotic turn-over at the thrombus site” (4:202-205).

ischemic cerebrovascular diseases (transient ischemic attack(TIA) and cerebral infarction) (13).

With clinical trials using aspirin as a control drug
confirming the superior platelet aggregation inhibitory effect

The pharmacological mechanism of action of aspirin was
found to be due to inhibiting COX-1 by irreversiblyof ticlopidine as well as its utility against peripheral arterial
occlusive diseases, the drug was put to market in 1981. Later

acetylating serine residue at cyclooxygenase-I (COX-I)
active centers. As a result, the production of thromboxane A2

clinical trials also demonstrated its utility on ischemic brain
injuries, including transient cerebral ischemia, cerebral(TXA2: promotes the cluster formation necessary to rapid
thrombus formation) downstream from COX-1 is inhibited,

infarction and cerebral ischemia in subarachnoid hemorrhage.
While it was France that discovered the medicinal efficacy of

thereby suppressing the aggregation of platelets. Since
platelets have no nucleus and new protein cannot be

ticlopidine, it was Japan and its research on antiplatelet
therapy that played the lead role in making the world aware

synthesized within the lifespan of a platelet (seven to tendays), acetylated COX-I remains inactive, thus continuingof its utility in this market. The term “antiplatelet”, coined by
Daiichi Pharmaceutical, is now a term commonly used thethe antiplatelet effect. Accordingly, excessive aspirin
treatment for inflammatory diseases or rheumatism canworld over. This concept is hugely significant in the field ofantithrombotics.

prolong bleeding time and at high concentrations has evencaused gastrointestinal bleeding and cerebral hemorrhage.

However, after some time in clinical use, despite its potent
efficacy, ticlopidine was found to have some side effects,

The antiplatelet action of aspirin varies between
individuals. In some patients, known as aspirin non

including thrombotic thrombocytopenic purpura (TTP),
agranulocytosis and hepatic dysfunction. Thus, the need

responders, it does not inhibit the biosynthesis of TXA2.
These patients are known to have a significantly higher risk

arose for new antiplatelet drugs.
A considerable number of Japanese antiplatelets thenof vascular death; in refractory cases, the precaution is taken
to change to other antiplatelets (14).

emerged in this field, with different mechanisms of action.
Dipyridamole is an antiplatelet that has long been used

In 1971, Daiichi Pharmaceutical, which had worked on a
joint project with Prof. Shosuke Okamoto and Mitsubishi

alongside aspirin. Researched and reported in 1951 by Fisher
and Roch, dipyridamole was marketed as an antianginal by a

Chemical in researching and developing the world’s first
antiplasmin (see 4.4.1. Hemostatics), embarked on another

German pharmaceutical company, Dr. Karl Thomae. It waslater found to suppress platelet aggregation and for over half

blood-related project: platelet aggregation inhibitors. It waspredicted that as time went on, there would be increasinga century it has been widely used around the world to treat
cerebral infarction and the like. Its effect on platelets is todemand for antithrombotics.
Daiichi Pharmaceutical devised a platelet measuring

prevent the cAMP catabolic enzyme phosphodiesterase(PDE), thereby elevating the platelet cAMP level anddevice and started screening, but no lead compound was
readily forthcoming. Instead, the company turned its

suppressing aggregation. In Japan, it was released on themarket by Nippon Boehringer Ingelheim as a treatment for

attention to ticlopidine, discovered by French company
Parcor (now Sanofi-Aventis) a short time before, in 1974,

coronary artery disease in 1960.
However, the results of recent large-scale clinical trials inand decided to introduce it. Using animal experiments, theresearch team at Daiichi Pharmaceutical found that rats

the West have disproven the efficacy of dipyridamole as an
antiplatelet. As a result, the discussion needs to be had as toadministered ticlopidine had elevated platelet cAMP levels,
but no changes in other organs. Later research showed thatwhether it can be adapted for the Japanese (14, 15).
Cilostazol (Otsuka Pharmaceutical) is a domestic productmarketed in 1988. Like dipyridamole, it prevents the cAMP
catabolic enzyme phosphodiesterase (PDE), thereby
elevating the platelet cAMP level and suppressing
aggregation. It was approved for its improvement in ischemic
symptoms from chronic arterial occlusion. Randomized
controlled clinical trials have also confirmed its utility in thesecondary prevention of cerebral infarction.
Limaprost alfadex (PGE1 derivative) (Ono Pharmaceuticaland Dainippon Pharmaceutical) was also launched in 1988.

ticlopidine in the body metabolizes into an active substancethat has an inhibitory effect on the platelet ADP receptors(ADP enhances inhibitory G-protein activity, which inhibits
adenylyl cyclase) and also prevents platelet aggregation by
maintaining cAMP at high concentration levels.
The company history Daiichi Seiyaku Kyūjū-nen-shi(90-year History of Daiichi Pharmaceutical) records thatwhile the initial question was to determine whether“inhibiting platelet aggregation actually produces an

110

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchThis unique antiplatelet was researched and developed
jointly by two Japanese companies, with research carried out
by Ono Pharmaceutical, with its track record in prostaglandin
research, and development carried out by Dainippon
Pharmaceutical. When administered orally, it demonstrates avasodilation effect and an antiplatelet effect by binding to the
PGE receptors to activate adenylyl cyclase and elevate thecAMP levels. It is more active in the body than the ligand
PGE1 and has been clinically adapted for peripheral arterial
occlusive disease.
Another drug with a similar mechanism of action but isclassified as a vasodilator is alprostadil (PGE1 intravenous
injection), developed by Green Cross Corporation (nowMitsubishi Tanabe Pharma) and Taisho Pharmaceutical andreleased on the market in 1988 for peripheral arterial
occlusive disease. Devised by Prof. Yutaka Mizushima of the
University of Tokyo’s Faculty of Medicine, the drug
comprises a lipoated (lipo PGE1) formulation of PGE1
dissolved in fine fat emulsion particles, where the fat
emulsion particles are used as carriers for the PGE1. Since
the fine emulsion particles can be easily distributed,
particularly by damaged blood vessels, PGE1 can beaccumulated efficiently at lesion sites. Being difficult toinactivate in the body, it demonstrates superior efficacy insmall doses. This formulation was developed using the drugdelivery system (DDS) idea. It has proven to be effective at¼ to ⅛ the dosage of conventional PGE1 formulations.
Prostacyclin (PGI2) is an endogenous biologically active
substance with a strong platelet aggregation inhibitory effectand a vasodilation effect, discovered by John R. Vane et al.
of the Wellcome Research Laboratories (nowGlaxoSmithKline) in the United Kingdom in 1976 (17). His
achievements with prostaglandin earned Vane the Nobel
Prize in Physiology or Medicine in 1982, along with Bengt
Samuelsson, discoverer of leukotrienes, and Sune Bergström,
who determined the structures of prostaglandins E1 and F1,for “their discoveries concerning prostaglandins and related
biologically active substances”.
Wellcome (now GlaxoSmithKline) trialed prostacyclin asa drug in the hope that systemic administration would
prevent thrombus formation; however, this was not
successful. In 1981, Wellcome obtained approval in the
United Kingdom to market epoprostenol (intravenously
injected prostacyclin) with efficacy limited to use as an
anticoagulant in extracorporeal circulation during renal
dialysis. Approval was given in Japan for its use on primary
pulmonary hypertension in 1999 and on pulmonary arterial
hypertension in 2004.
Meanwhile, Japanese research on PGI2 derivatives
continued. PGI2 derivative beraprost, research and developed
by Japanese companies (Toray / Kaken Pharmaceutical) was
released on the market in 1992. This antiplatelet
demonstrates a PGI2 effect, inhibiting the aggregation ofplatelets by activating adenylyl cyclase on the membrane toelevate cAMP levels. It was approved, indicated for“improving ischemic symptoms accompanying chronicarterial occlusion”.
Ozagrel is a selective TXA2 synthase inhibitor researchedand developed jointly by Ono Pharmaceutical (Note 7), with its
strong track record in the area of prostaglandins, and Kissei
Pharmaceutical. While inhibiting TXA2 inhibits platelet
aggregation, it does not inhibit PG-endoperoxide, which has
a powerful aggregation action. As a result, it does notcompletely inhibit arachidonic acid aggregation and collagenaggregation, but it does inhibit spasms caused by TXA2.
Approval was granted in 1988 for improving cerebral
vasospasms following surgery for subarachnoid hemorrhage
and accompanying symptoms of cerebral ischemia. In 1992,
additional adaptation approval was given for this injecteddrug for improving dyskinesia accompanying cerebral
thrombosis. An orally-administered version of the drug was
also developed, but it was more trouble to find a target
disease for this than the injected drug. Experiments on dogs
demonstrated efficacy against bronchial hyperreactivity;
following clinical trials, the drug was marketed as atreatment for bronchial asthma in 1992 under the brand nameof Vega®.
The antiplatelet Sarpogrelate, marketed by Mitsubishi
Chemical in 1993, used a new mechanism to inhibit platelet
aggregation: that of antagonizing serotonin at the serotonin II
receptors on the platelet membrane. Serotonin also causes
vasoconstriction, so it is considered clinically advantageous
to inhibit it. It is being adapted for use against peripheralarterial occlusive disease, although further evidence isdeemed necessary.
Clopidogrel, researched and developed overseas in 1988
by Sanofi Sante and Organon, has achieved majorcommercial success, valued second only to aspirinworldwide. Clinical development began in Japan in 1996 by
Sanofi Aventis, with approval granted in 2006 for efficacy in“preventing recurrence of ischemic cardiovascular disease(except cardiogenic embolism)”. In 2012, addition approval
was given for efficacy in “preventing thromboembolism inperipheral arterial disease”. This drug was created for the
purpose of alleviating the side effects from ticlopidine;clinically, it has “significantly lower incidence of side effects
such as liver damage and lower neutrophil count” thanticlopidine.
Another substance involved in the inhibition of platelet
aggregation is cAMP. The higher the cAMP level, the greater
the inhibition of platelet aggregation. cAMP isbiosynthesized by adenylyl cyclase (AC), while the ADP
receptors work to inhibit this enzyme. Clopidogrel has beenfound to bind irreversibly to the ADP receptors, thereby
preventing the inhibition of adenylyl cyclase and increasing
the cAMP level (15). (see Figure 4.24 Platelet Aggregationand Mechanism of Action of Antiplatelets and Figure 4.25
Chemical Structures of Antiplatelets)

Systematized Survey on the History of Drug Discovery with Technical Development

111

Activation signal
Inhibitory signal

Serotonin
Cilostazol

ThrombinCollagen
Adrenaline

Adenylyl cyclase

Arachidonic acidCa2+
concentration

AspirinTXA2 synthase

ATP ADP
Serotonin
Fibrinogen

OzagrelDegranulation
Source: Umezu 2014

Platelet aggregation mechanism When the vascular wall is damaged, collagen is released from the vascular wall and binds to vWF factor produced by
the endothelial cells. Platelets bind to this by means of their GPIb receptors. When this occurs, the platelets adhere to
the endothelial tissue and stasis occurs. This is called primary hemostasis or primary aggregation.
 Where platelets adhere, the signal transduction system is activated. Intracellular Ca2+ levels elevate due to increases in
TXA2 and decreases in cAMP. As a result, degranulation occurs, with extracellular release of ADP, serotonin andthrombin contained in the granules. These activators secondarily active the surrounding platelets, causing the GPIIb/IIIa
receptors to be expressed on the surface of the platelets. These receptors connect with fibrinogen and theaforementioned vWF factor, and secondary platelet aggregation occurs.
 Meanwhile, extrinsic coagulation initiator tissue factor (TF) binds with VIIa to activate the blood coagulation cascade.
Mechanism of Action of Antiplatelets[Receptor Antagonists]
As receptor antagonists, ticlopidine acts on ADP receptors () and sarpogrelate acts on serotonin receptors ().
[cAMP Agonists]
PGI2 and PGE1 () elevate intracellular cAMP levels. Cilostazol elevates cAMP levels by inhibiting cAMP
catabolic enzymes ().
[Arachidonate Metabolism Inhibitors]
Aspirin inhibits COX (); ozagrel inhibits TXA2 synthesis (); EPA activates the ω3 system and inhibits the ω6
system, thereby suppressing signal transduction and the increase of Ca, thus inhibiting platelet aggregation ().

Fig. 4.24 Platelet Aggregation and Mechanism of Action of Antiplatelets

Beraprost: Elevates cAMP levels
via the IP receptors.
Dipyridamole: Elevates cAMPlevels by inhibiting catabolic
enzymes.

Cilostazol: Elevates cAMP levels
by inhibiting catabolic enzymes.

Limaprost alfadex: Elevates cAMPlevels via the IP receptors.

Ticlopidine (hydrochloride): Inhibits signaltransduction by antagonizing ADP at ADP
receptors. Elevates cAMP concentration.

Clopidogrel (sulfate): Inhibits signaltransduction by antagonizing ADP at
ADP receptors, consequently elevatingcAMP concentration.

Sarpogrelate: Antagonizes
serotonin receptors.

Fig. 4.25 Chemical Structures of Antiplatelets

112

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchEpidemiological studies in the 1970s found that theand the like produces arachidonic acid and also

indigenous population of Greenland, whose staple food is thebiosynthesizes prostaglandin (PG) and thromboxane (TXA),

seal, were found to have a lower mortality rate fromsubstances that cause or are involved in inflammation, while

cardiovascular diseases than Danish Caucasians, as

the ω-3 in α-linoleic acid also synthesizes PG and TXA.

mentioned in 4.3.2 (Natural Hyperlipidemia Medications).

Prolonged ingestion of EPA-E replaces the phospholipid

Research into the cause of this concluded thatarachidonic acid (AA) on the platelet membrane with EPA.

eicosapentaenoic acid (EPA), which is found in ample supply

While EPA, like AA, forms a phospholipase A2 substratein the blubber of seals and fish, suppresses cardiovascularand joins the prostaglandin cascade, EPA produces PGI3 anddiseases through an antiplatelet effect.

TXA3, rather than the PG2 and TXA2 produced by AA.

In 1980, Nippon Suisan Kaisha became the first in the

Although PGI2 and PGI3 have similar effects, TXA3 lacks theworld to successfully refine eicosapentaenoic acid from fish

powerful platelet aggregation effect of TXA2. Accordingly,

oil to a high level of purity (over 85%) by ethyl esterification.

people taking EPA will have slightly inhibited platelet

In 1981, the company began developing eicosapentaenoic

aggregation (see Figure 4.26).
This moderate effect and the lack of side effects areacid ester (EPA-E) into a pharmaceutical product in capsuleform, in collaboration with Mochida Pharmaceutical. EPA-E

significant characteristics of this drug. In 1994, approval was

was approved for “alleviating ulcers, pain and cold sensation

extended, indicated for hyperlipidemia.
Research and development has also been carried out onaccompanying arteriosclerosis obliterans”. This unique idea

GP IIb/IIIa inhibitors and plasminogen activator inhibitor-1

of creating a drug from fish oil deserves recognition.
Basic research was conducted to analyze the antiplatelet(PAI-1), necessary for platelet adhesion, as anticoagulants.

effect of EPA-E. It was found that the ω-6 in linoleic acid

Linoleic acid (ω-6)α-linoleic acid (ω-3)
5-lipoxygenase
5-lipoxygenase

Arachidonic acid

Eicosapentaenoic acid

Cyclooxygenase
Cyclooxygenase

Leukotrienes

Leukotrienes

Source: Umezu 2014

 Production of prostaglandin (PG) and leukotrienes (LT) from linoleic acid  by means ofarachidonic acid is the route taken by ω-6, while ω-3 produces PG and leukotrienes from
α-linoleic acid  by means of eicosapentaenoic acid.
 In A, arachidonic acid and eicosapentaenoic acid are converted to PGG2 and PGG3 bycyclooxygenase (COX). In B, 5-lipoxygenase converts arachidonic acid and eicosapentaenoic
acid into (several kinds of) leukotrienes .
 TXA2, PGE2 and PGI2 are present downstream from PGH2 (//) and are closely
involved in inflammation, clotting and vasodilation. Leukotrienes are closely involved in allergy
symptoms.
 ω-3 PG and TXA differ from their ω-6 counterparts in that they have no inflammation-inducing
or thrombus-promoting effects.

Fig. 4.26 Arachidonic Acid Cascade and EPA Cascade

Systematized Survey on the History of Drug Discovery with Technical Development

1134.4.4.

Fibrinolytic Drugs

Coagulation involves the coagulation system and theindications for “alleviating functional disorders
accompanying acute-phase ischemic cerebrovascular disease

fibrinolytic system. Since activation of the fibrinolytic(within three hours of onset)”. This was the drug known assystem breaks down thrombi, inhibiting the coagulation

alteplase. In 1996, Mitsui Toatsu, Mitsui Chemicals andsystem not only inhibits thrombus formation, but is also

Mochida Pharmaceutical expressed human fibroblast t-PA

believed to activate the fibrinolytic system, which promotes

from mouse cells and developed this as nateplase.

the breaking down of thrombi.
In 1933, William S. Tillett discovered the effects ofstreptokinase by chance. This was put to use as early as 1958

Asahi Kasei and Kowa produced t-PA by tissue
cultivation and marketed this in 1991 as tisokinase.
In 1986, Eisai started researching t-PA derivatives with aon patients with acute myocardial infarction. Streptokinase islonger biological half-life that could be administered as aa protein excreted from the cells of the hemolytic

single intravenous injection. After investigating converting

streptococcus pyogens. When administered to humans in vivo,

t-PA into an amino acid sequence using gene recombination

it demonstrates a specific serine protease action, forming atechnology, the company selected a chimpanzee derivativecomplex with plasminogen. This acts on plasminogen to

known to produce no antibodies (with the amino acid residue

convert it into plasmin, which stimulates the fibrinolytic

Cys in 84th position from the N-terminus of t-PA replaced

system. Due to its low cost, it was used in the West forwith Ser) as a candidate compound for clinical development.

myocardial infarction and pulmonary embolism (Note 8),

Clinical trials confirmed this t-PA derivative to have fibrin

although it has largely fallen out of use due to significant

bonding properties and a sustained thrombolytic effect. In

issues with side effects from antigens, with human t-PA and

1998, approval was granted for “breakdown of coronary

other drugs being developed in its place.

thrombi associated with acute myocardial infarction (within

Fibrinolytic system activating factors include

six hours of onset)”. The drug was released on the market inurokinase-type plasminogen activator (u-PA), discovered inJune the same year, nine years after clinical trials began. Thisurine in 1947, and tissue-type plasminogen activator (t-PA).

was the thrombolytic drug known as monteplase.

Both stimulate fibrinolysis by activating plasminogen and

In 1999, Yamanouchi Pharmaceutical started marketing

converting it into plasmin. The major difference between

pamiteplase. Pamiteplase is an improved drug with a longer

these two enzymes is their fibrin specificity. t-PA activates

than natural acting time, with the t-PA kringle-1 removed byplasminogen on fibrin thrombi by binding with fibrin

gene manipulation and Arg in 275th position substituted formolecules, while the plasmin produced efficiently breaks

Glu.

down the fibrin.
By contrast, u-PA has little fibrin affinity, instead

Note 1: “Intrinsic coagulation” refers to coagulation that occurs bybreaking down thrombi by activating blood plasminogen into

the activation of coagulation factors due to causes within a bloodplasmin. Consequently, u-PA has limited use in treatment.

vessel. “Extrinsic coagulation” refers to coagulation that occurs

As a product, urokinase refined from human urine waswhen thromboplastin from externally damaged tissue binds to Factor

developed and marketed by Green Cross and Mochida

VII and activates it (FVIIa). FVIIa then directly activates Factor X

Pharmaceutical in 1983 (Note 9). Urokinase refined from(FX) into (FXa) in the presence of Ca2+. After that, fibrin formation

human renal cell tissue culture was developed by Dainippon

occurs as it does for intrinsic coagulation.

Pharmaceutical and Mitsubishi Petrochemical under licensefrom Abbott and launched on the market in 1983. Green

Note 2: There are two phases of platelet aggregation: primary

Cross developed nasaruplase, a urokinase precursor withaggregation, in which platelets adhere to vascular subendothelial

greater fibrin affinity, and obtained approval for it in 1991

tissue to cause stasis, and secondary aggregation, which occurs when

(18)

.

various biologically active substances released from the activated

Unlike u-PA, t-PA can be mass-produced through genetic

platelets activate surrounding platelets. Primary hemostasis andengineering. A more stable second-generation t-PA has been

secondary hemostasis are hemostatic effects in the coagulation

produced by altering some of the genes.

cascade.

Human t-PA was refined by Collen in 1981. The
following year, U.S. company Genentech successfully mass
produced it using genetic engineering technology. In Japan,

Note 3: Heparin is a mucopolysaccharide sulfate with an
anticoagulation effect in the body. For details, see 4.4.2.

it was licensed to Mitsubishi Chemical and clinicallydeveloped in collaboration with Kyowa Hakko, gaining
approval in 1991 as a “thrombolytic for acute myocardial
infarction”. In 2005, approval was extended to include

114

Note 4: Antithrombin III was termed antithrombin by theInternational Society on Thrombosis and Haemostasis in 1994. It
was originally thought that antithrombins I to VI were present in thebody, but in fact only III is present.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchNote 5: Drugs to inhibit thrombin include gabexate mesilate andnafamostat mesilate. These were approved in 1977 and 1986 astreatments for acute pancreatitis; their indications were extended in
1989 for disseminated intravascular coagulation (DIC). However,with a mechanism of action due to inhibiting a wide range of “serine
proteases”, including trypsin, kallikrein, plasmin and thrombin, they
were not specific inhibitors.

derivatives of Nα (arylsulfonyl)-L-arginine. Journal of
Medicinal Chemistry 23:827-830 (1980)[7]

Kikumoto R., Tamao Y., Okamoto S. et al.: Selective
inhibition of thrombin by (2R,
4R)-4-methyl-1-[N2-(3-methyl-1,2,3,4tetrahydro-8-qui
nolinyl) sulfonyl]-L-arginyl]-2-piperidinecarboxylic
acid. Biochemistry 23:85-90 (1984).

Note 6: Disseminated intravascular coagulation (DIC) is a disorderin which endotoxins and the like produce abnormal stimulation of
the coagulation system, thereby activating the proinflammatory
cytokine network, resulting in the overproduction of thrombin andthe repeated formation of thrombi in microvascular endothelial cells
throughout the body. This leads to ischemic organ dysfunction.

[8]

Effect of a synthetic thrombin inhibitor MCI9038 on
experimental models of disseminated intravascular
coagulation in rabbits. Thrombosis and Haemostasis
57:165-172 (1987).
[9]

Note 7: Ono Pharmaceutical has worked entirely on “prostaglandin(PG) research and development” since 1965, at the discretion of thecompany president at the time, Yuzo Ono. This was five to ten years
before prostaglandin gained attention due to work by Nobel laureates
Vane, on inflammation and PG, and Samuelsson, on TXA2 andleukotrienes. Ono Pharmaceutical later went on to market 12 new
products related to PG. Between 1974 and 1979, the company
commercialized pharmaceutical products from natural PG,
marketing the world’s first PG oxytocic PGF2α in 1974 and PGE2 asa uterotonic in 1976. Between 1984 and 1988, the company
commercialized derivative pharmaceutical products, marketing PGE1
derivative limaprost alfadex for peripheral arterial occlusive diseasein 1984 and TXA2 synthesis inhibitor ozagrel and leukotriene
receptor inhibitor pranlukast between 1988 and 1995. Much can belearned from this company’s conviction and endeavor in repeatedly
taking on new, uncharted fields and creating products in all kinds ofareas.

Hara H., Tamao Y., Kikumoto R. & Okamoto S.:

Ruff C.T., Giugliano R.P., Braunwald E. et al.
Comparison of the efficacy and safety of new oral
anticoagulants with warfarin in patients with atrial
fibrillation: a meta-analysis of randomised trials.
Lancet 383:955-962 (2014).

[10] Imai N., Fujii Y. & Amano M.: Keikō FXa Sogai-yaku
Apixaban (Eliquis®) no Yakurigakuteki Tokusei to
Rinshō Kōka. Folia Pharmacologica Japonica
142:247-256 (2013).
[11] Perzborn E., Misselwitzet F. et al.: The discovery anddevelopment of rivaroxaban, an oral, direct factor Xa
inhibitor. Nature Reviews Drug Discovery 10: 61-75(2011).
[12] Weiss H. J. & Aledort L.M.: Impaired platelet/
connective tissue reaction in man after aspiriningestion. Lancet 2:495-497 (1967).

Note 8: Although streptokinase is indicated for removing hematoma
in Japan, it is not sold for its indication as a thrombolytic.
Note 9: Urokinase from urine was approved in 1965 indicated forthromboembolism, but it has come under review as a pharmaceuticalproduct because the dosage differs significantly from the West andthere is doubt as to its efficacy.

[13] Iyakuhin Intabyū Fōmu (Drug interview form).
“Bayaspirin (9th edition)”. Bayer Pharmaceuticals(2008).
[14] Digest version: Junkanki Shikkan ni okeru Kōgyōko /Kōkesshōban Ryōhō ni Kansuru Gaidorain(Guidelines on Anticoagulation/Antiplatelet Therapy in
Cardiovascular Disease). Team leader: Hori M. 11(revised 2009).

References[1] Harvey R. A., Maruyama K. & Yanagisawa T. (sup.
trans.): Illustrated Pharmacology, 5 Volumes.
Maruzen Publishing (2012).
[2] Takeuchi K. & Oka J. (eds.): Saishin Kiso Yakurigaku(Latest Basic Pharmacology). Hirokawa Publishing(2011).
[3] Okamoto S. (ed.), Kikumoto R., Takao Y., Otsu K. etal.: Sekai wo Ugokasu Nihon no Kusuri (Japanese
Medicine to Move the World). Tsukiji Shokan (2001).
[4] Daiichi Seiyaku Kyūjū-nen-shi (90-year History ofDaiichi Pharmaceutical). Daiichi Pharmaceutical Co.,
Ltd. (2007).
[5] Mitsubishi Kasei-sha-shi (History of Mitsubishi Kasei
Corporation). Mitsubishi Chemical Corporation(1981).
[6] S. Okamoto, R. Kikumoto, Y. Tamao et al.: 1. Ester[15] Gotō S. (ed.): Kōgyōko / Kōkesshōban Ryōhō(Anticoagulant/Antiplatelet Therapy). Ishiyaku
Publishers Update: 7-14 (2010).
[16] Iyakuhin Intabyū Fōmu (Drug interview form).
“Thrombomodulin Alpha (GM)”. Asahi Kasei Pharma(2013) (9th revision).
[17] Vane J. R.: Inhibition of prostaglandin synthesis as amechanism of action for aspirin-like drugs. Nature
New Biology 197:232-235 (1971).
[18] Ozawa H., Abiko Y. & Akimoto T.: Shinyaku
50-nen-shi (Shiketsuyaku oyobi Kōkessenyaku) (50Years of New Medicine (Hemostatics andAntithrombotics)). The Japanese Journal for History of
Pharmacy 38 (1):93-108 (2003).

Systematized Survey on the History of Drug Discovery with Technical Development

115

4.5 Medications for Gout/Hyperuricemia

characterized in that it becomes extremely painful within ashort period from onset.

According to the 2004 Comprehensive Survey of Living

Uric acid, which causes gout, is synthesized from theConditions by the Ministry of Health, Labour and Welfare,metabolism of DNA/RNA structural components adenine

the total number of patients receiving treatment for gout was

and guanine (called purine bodies due to their chemical

870,000, around double the 1995 figure. The number ofstructures) into hypoxanthine and xanthine, which are thenpeople with hyperuricemia, which could be termed asconverted into uric acid through the action of oxidoreductase(1)pre-gout, could be as high as 10 million .

xanthine oxidase.

According to Hippocrates of ancient Greece, gout is a

Hypoxanthine-guanine phosphoribosyl transferase

disease accompanied by intense pain even when the wind

(HGPRT) is a reverse metabolic pathway enzyme thatblows. He observed and recorded a number of accurate facts

prevents the overproduction of uric acid. Patients withas a physician, including that castrated men do not suffer

Lesch-Nyhan syndrome hereditarily lack this enzyme andfrom gout, that it does not occur in women until after

have abnormally high levels of uric acid (see Figure 4.27

menopause, that even in men, it does not occur until a more

Uric Acid Biosynthesis Pathway and Synthesis Inhibitors).

mature age, that the inflammation subsides within 40 days
and that gout is more active in spring and fall (2).

Nucleic acid

Dioscorides (mentioned previously), a military physician
Adenineunder the Roman emperor Nero, also recorded 2000 years
ago in his work De Materia Medica that willow bark (Note 1)

GuanineBoth adenine and guanine
become uric acid via xanthine.
Inhibiting xanthine oxidase
prevents the production of uricacid.
Allopurinol has a similar structure
to uric acid, while febuxostat has
a different structure.

Inosinic acidand meadow saffron (Colchicum autumnale) were effective
against gout.
Hypoxanthine

Xanthine

Many notable people in Western history suffered fromgout. According to the Gout Research Foundation, these

Uric acid

Xanthine
oxidaseinclude Alexander the Great, Louis XIV of France, Martin
Allopurinol

Luther, Francis Bacon, Isaac Newton, Charles Darwin,

Febuxostat

Goethe, Stendhal and Guy de Maupassant (2:5, 3). By contrast,
the disease was unknown in Japan until the Meiji Period.
Luís Fróis, a Portuguese missionary during the
Azuchi-Momoyama Period, wrote that “there is no goutamong the Japanese”. It seems that the disease suddenly
appeared in the Meiji Period. Gout sufferers began to rapidly
increase in number in the 1960s, presumably as a result ofchanges in diet.
When the level of uric acid in the blood and tissue fluid
rises above the saturation point (7.0mg/dl), monosodium
urate is deposited into the tissue in crystalline form. While
the kidneys and joints are susceptible to a build-up of thesecrystals, the base joint of the big toe is particularly
susceptible to this build-up, with initial onset occurring at
this site in 70% of cases. The deposited crystals eventuallyleak into the synovial fluid and are attacked by inflammatory
leukocytes as foreign contaminants. Although leukocytes
ingest uric acid through phagocytosis, they have no
mechanism for breaking down the crystals; thus, thelysosomes (intracellular organelles, including catabolic
enzymes) become damaged and the enzymes leak out. At thesame time, the leukocytes also release cytokines and otherinflammatory biologically active substances. These released
substances (prostaglandin, proteinase and reactive oxygen)

Fig. 4.27 Uric Acid Biosynthesis Pathway and Synthesis
Inhibitors
Uric acid is synthesized in the body and also derived fromfood; it is excreted from the body with the urine and feces,although some is retained to maintain steady uric acid levelsin the body. Around 80-90% of uric acid in humans is
synthesized in the body, while the remaining 10-20% isderived from food.
Since such a small amount of uric acid is food-derived, it
is difficult to explain why there was no gout in Japan until
the Meiji Period. Perhaps it was not only the Japanese dietthat changed, but also the internal metabolism due to changes
in living environment. Perhaps the Japanese started secreting
more male hormones and adrenaline in the Meiji Period of
wealth, military strength and industry promotion?
Most gout sufferers are males in their 30s and 40s,
although recent years have seen an increase in younger
patients. There are far fewer female patients due to the factthat female hormones help to excrete uric acid from thebody; accordingly, there are higher uric acid levels among
postmenopausal women. Uric acid levels in males are known
in to increase with puberty.

act as attractants, causing an inflammatory reaction the sameas in other tissues. Gout-related inflammation is

116

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchIf the uric acid metabolism becomes unbalanced for somethe United States Pharmacopeia as being “extremely toxic” (5).

reason, the uric acid level in the blood increases, resulting in

However, colchicine is a specific medicine for gout pain andhyperuricemia. There are two causes for this: (i) excessive

is still used in the West as a first-line drug. The

production of uric acid; (ii) reduced excretion of uric acid.

pharmacological effect of colchicine is known to be due toAround 60% of Japanese patients fall into the second

preventing the formation of microtubules by binding tocategory. Uric acid excretion reduces with deterioration in

tubulin, the main protein in microtubules. It is also known tokidney function due to arteriosclerosis, hypertension,

have an anti-inflammatory effect by preventing neutrophil

diabetes or nephritis. However, it has also been suggested

activity (migration and activation). This anti-inflammatorythat Japanese have hereditarily low uric acid excretion.

effect is specific to gout and has no effect on arthritis or

Vigorous exercise, stress, excessive drinking, obesity,

rheumatism; its mechanism of action is not yet clearly

medications (diuretics or immunosuppressants) andknown.

hereditary factors can all cause excessive uric acid

In Japan, corticosteroids and colchicine are also used as

biosynthesis and can also cause reduced uric acid excretion.
Since hyperuricemia, a pre-symptom for gout, is not

the main non-steroidal anti-inflammatory drugs for gout
attacks. Non-steroidal drugs include indomethacin, naproxen,
oxaprozin and pranoprofen (6).

accompanied by pain or other subjective symptoms, its
detection is often delayed. This is also true of otherlifestyle-related diseases, such as hypertension,

4.5.2.

hyperlipidemia and hyperglycemia, which also show no

Medications for Hyperuricemia

The intermittent gout stage involves recurring gout attacks

subjective symptoms.

with intervening remission. Many patients stop taking their

The disease progresses from asymptomatic hyperuricemia

medication when the pain stops. There has been little

to a period of intermittent gout (a stage of recurring goutawareness of the need to treat hyperuricemia and very few

attacks), then followed by chronic gout accompanied bytreatment options for it. However, with growing awarenessconstant pain and the formation of tophi. Variousthat hyperuricemia is a pre-symptom for gout and that uriccomplications occur, including gouty kidneys, hypertension

acid levels need to be lowered at this stage, active measuresand hyperlipidemia. Accordingly, it is important to treat

have been taken in the 21st century for drug treatment as well

hyperuricemia before it gets to that stage. For example, a

as improved lifestyles and dietary cures. Japanese drug

comparison between treated and untreated groups of

discovery companies have contributed to research andasymptomatic hyperuricemia patients found a 0% incidence

development of new hyperuricemia drugs that either inhibit

rate of urinary tract stones during 44 weeks of observation

the biosynthesis of uric acid or promote its excretion.

among the treated group compared to a 7.6% incidence rate
among the untreated group (4). It has recently been found that

Uric Acid Production Inhibitors

obese people have a higher incidence rate of gout. There is

The cause of gout is clear. Allopurinol, which inhibits

ongoing discussion on the progression of hyperuricemia due

xanthine oxidase, essential for uric acid production, has longto metabolic abnormalities caused by visceral fat

been used to treat gout. Allopurinol was discovered byaccumulation. Gout is now included among theGertrude Belle Elion (Note 2) and George Herbert Hitchings oflifestyle-related diseases collectively termed as metabolic

British company Wellcome Research Laboratories. In 1957,

syndrome (1). There is another theory that uric acid levels in

it was found to have a xanthine oxidase inhibitory effect in

the blood can be used as a biomarker for early diagnosis ofvitro (7).

metabolic syndrome, since this is affected earlier than othermetabolic syndrome indicators.

Allopurinol was trialed in concomitant administration
with anti-tumor agent 6-mercaptopurine, which was known
to lose its activity due to the effects of xanthine oxidase.

4.5.1.

Rundles et al. then discovered that it lowered the uric acid

Medications for Goutlevel in the blood and urine (8). Since then, it has been

The seeds and bulbs of meadow saffron Colchicum
autumnale have been used to treat gout since ancient Greece.

administered for gout and hyperuricemia. In Japan, Tanabe

Its active ingredient colchicine was first isolated in 1820 by

Seiyaku licensed it from Wellcome and started selling it inFrench chemists Pierre Joseph Pelletier and Jean Bienaimé

1969 under the name of Zyloric® (9, 10).
With little sales of gout medications in Japan, there were

Caventou (mentioned previously: 2.2.1.).
While colchicine has demonstrated superior efficacy as afew drug discovery companies getting involved in the market.

medication for gout, in 1937, American botanist AlbertWith no successor to allopurinol for 40 years, treatment

Blakeslee found the substance to induce the doubling ofoptions were limited. In 2011, Teijin Pharma launchedchromosomes in plant cells. Highly toxic, it was reported bydomestically-produced febuxostat. Where allopurinol has a

Systematized Survey on the History of Drug Discovery with Technical Development

117purine analog structure, febuxostat is a non-purine compoundwith a characteristically powerful inhibitory effect on
xanthine oxidase (11). Another feature of this compound is

Allopurinol
Released in Japan in 1968
The only uric acid synthesis inhibitorfor 40 years

that it is almost completely excreted in the feces and urine
Colchicine

once metabolized by the liver, meaning that it can be

Used by the ancient Greeks as a
remedy for gout and still actively
used today

administered at full dosage even for patients with impaired
renal function. Although it was marketed in the United Statesin 2009, earlier than in Japan, even there it was the first uricacid production inhibitor in 40 years. It was released inEurope in 2010.
Teijin (now Teijin Pharma) embarked on its own drug
Topiroxostat

discovery research in 1988 and discovered the new
non-purine drug febuxostat in 1991. According to Shinyaku

Released in 2013
Domestic product created by Fuji
YakuhinFebuxostat
Released in 2011
Japan’s first uric acid synthesis inhibitor
in 40 years
Domestic product created by Teijin
Pharmani idonda Nihonjin Kagakushatachi (Japanese Scientists who
Strove for New Medicine) by Asako Tsukasaki, “theFig. 4.28 Colchicine and Uric Acid Production Inhibitors

synthesist Shira Kondo retreated from the field in which the
major players were competing with topic setting and opted
for the medium-scale market. However, there were a lot of

Uricosurics

patents in the area of gout, more than 50 of them better than

Uric acid in the blood is 100% filtered by the glomeruli inallopurinol, but none of them had been developed into drugs.

the kidneys. Once it has been reabsorbed by the uriniferous

Kondo et al. knew that allopurinol inhibited xanthine oxidase

tubule, it is again secreted to the uriniferous tubule and thenthrough a more complex mechanism of action than Elion andexcreted into the urine after being absorbed once more (theHitchings had envisaged, so they steered away from the basic

four-component model). The uric acid that is finally excreted

purine structure and created a mother nucleus that formed ainto the urine is around 6-10% of the volume that was

non-purine consensus structure. Eventually, febuxostat was

filtered.

synthesized and was found to firmly embed itself in the
pocket of the enzyme usually occupied by hypoxanthine”.
While allopurinol is excreted from the kidneys, febuxostat

The epithelial cells of the proximal renal tubule near theglomeruli have a transporter for uric acid called uric acidtransporter 1 (URAT1). This transports uric acid from theis metabolized by the liver and excreted in the feces anduriniferous tubule into the blood vessels in exchange forurine, requiring less work by the kidneys. The drug wasorganic anions (such as negatively-charged amino acids,

marketed in the United States in 2009, Europe in 2010 andlactic acid and nicotinic acid). This constitutes the reuptake

Japan in 2011. This was Japan’s first drug to be indicated forof uric acid from the urine into the blood. Inhibiting URAT1

hyperuricemia.

suppresses the reuptake of uric acid, thereby promoting its

Although clinical trials of febuxostat began in 1995, it was
not until 2011 that the clinical trials came to a close and theexcretion from the blood and reducing the amount of uricacid. URAT1 is a target for uricosurics.

drug was put to market. It had been 23 years since research

Uric acid is again secreted from the blood into the urine

began and 16 years since clinical trials began. While it wasby the uriniferous tubule. After that, it is reabsorbed into the

not rare for clinical trials to take more than ten years in Japan,

blood by the uric acid transporter. The reuptake of uric acidwith the advent of the age of internationalization in the latteris inhibited if the transporter is suppressed.

thhalf of the 20 century, doubts began to arise over the way
clinical trials and approval reviews were being done.
Fuji Yakuhin came up with a new drug to inhibit xanthine

Probenecid was originally used as a drug to inhibit theexcretion of penicillin. This drug contributed to research on
the activity duration of the new antibiotic penicillin duringoxidase selectively and reversibly: topiroxostat. Clinicalthe Second World War. Interestingly, the main uric aciddevelopment started in 2004, with Sanwa Kagaku

production inhibitor allopurinol, mentioned above, was alsocollaborating from phase III trials onwards. The drug wasused for maintaining the efficacy of antitumor drugs. The

approved in 2013 and sales commenced.

indications for probenecid were later expanded to include

Figure 4.28 shows the chemical structures ofrepresentative hyperuricemia drugs.

hyperuricemia.
The main mechanism of action of probenecid is known tobe due to inhibiting the initial reuptake of uric acid secreted
from the uriniferous tubule. Due to its pharmacological effect,
probenecid is known to affect the metabolism of a number of118

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.Marchdrugs, including antibacterials, and concomitantadministration needs to be undertaken with care. It has also
long been used as a basic pharmacological research tool for
its properties.
Most other uricosurics developed later inhibit the reuptake
Probenecidof uric acid after secondary secretion. In terms of medicinal

Uricosuric released in 1956

efficacy, the latter reuptake inhibitors are more potent.
Bucolome is a drug researched and developed in Japan asa non-steroidal anti-inflammatory drug (NSAID) and also
has a uricosuric effect. In a collaborative study with Hajime
Fujimura of Gifu University and Shigeo Senda of Gifu
Pharmaceutical University, Takeda Pharmaceutical

Bucolome
Released in 1967
Created by Gifu University, Gifu
Pharmaceutical University, Takeda
Pharmaceutical; marketed by Takeda
Pharmaceutical
Anti-inflammatory and uricosuric effects

investigated pyrazolidenedione derivatives and peripheral
compounds and discovered this compound, which has bothanti-inflammatory and uricosuric effects. With few of theusual side effects of anti-inflammatories and no effects on
the kidneys, the drug was launched in 1967 as a uricosuric
suitable for prolonged administration.
Benzbromarone is a uricosuric developed by Torii
Pharmaceutical under license from French company Labaz.
The most potent of all uricosurics, it is the most widely used
today, as its long half-life of 18 hours allows it to retain its
uricosuric effect with once-a-day administration.
Known to inhibit uric acid transporter URAT1

Benzbromarone(13), it isLicensed from Labaz
Released in 1978 by Torii Pharmaceuticalalso believed to strongly inhibit secondary uric acid reuptake.
Not only is benzbromarone metabolized by
Fig. 4.29 Uricosurics

drug-metabolizing enzyme CYP2C9 to become an active
metabolite, it also has a CYP2C9 inhibiting effect.
Accordingly, care must be taken when used concomitantly

Interestingly, Japan has created many new drugs for goutwith other drugs, as the metabolism of other drugs

and hyperuricemia.

metabolized by CYP2C9 will be delayed, causing bloodconcentrations to elevate.
For example, blood concentrations are monitored when

Note 1: Strictly speaking, recent investigation has found that salicinusing the blood thinner warfarin and care must be taken with

was isolated from meadowsweet Filipendula ulmaria rather thanthe concomitant administration of benzbromarone due towillow bark. This is now presumed to have been ineffective againstconcerns over elevated blood concentration.

gout, although it did have an analgesic effect.

Since uricosurics increase the amount of uric acidexcreted into the urine, care must also be taken due to greater
susceptibility to uric acid stones in the kidneys, urinary
bladder and urethra.
Figure 4.29 shows the chemical structures ofrepresentative uricosurics.

Note 2: Gertrude Elion was awarded the Nobel Prize in Physiology
or Medicine in 1988, together with George Hitchings and James
Black (see 2.4.3), “for their discoveries of important principles for
drug treatment”. As well as allopurinol, Elion invented at least fiveother types of world-renowned new drugs, including
6-mercaptopurine, azathioprine and aciclovir.

References[1]

Hidaka Y.: Tsūfū/Kōnyōsanketsushō(Gout/Hyperuricemia). Takahashi Shoten 20-21(2014).

[2]

Kihara H.: Tsūfū (Gout). Chuko Shinsho (1990).

[3]

Gout Foundation website, accessed 2014.

[4]

Hosoya T., Kono H., Ikeda H. et al.: Mushōkō-sei

Systematized Survey on the History of Drug Discovery with Technical Development

119

Kōnyōsankesshō no Yogo ni Kansuru Kenkyū – I

[5]

[6]

Riumachi (Studies on the Prognosis of Asymptomatic“Salobel®”. Dainippon Sumitomo Pharma (revised

Hyperuricemia - I. Rheumatism). 25:369-371 (1985).

2011).

Taylor N., Nanba T. & Nanba Y. (trans.): Sekai wo[8][11] Takano Y., Hase-Aoki K., Horiuchi H. et al.:Kaeta Yakuyō Shokubutsu (Plant Drugs that Changed

Selectivity of febuxostat, a novel nonpurine inhibitor of

the World). Sogensha 300-306 (1972).

xanthine oxidase/xanthine dehydrogenase. LifeJapan Society of Gout and Nucleic Acid Metabolism

Science 76: 1835-1847 (2005).

(ed.): Kōnyōsankesshō / Tsūfū no Chiryō Gaidorain[7][10] Iyakuhin Intabyū Fōmu (Drug interview form).

[12] Tsukasaki A.: Shinyaku ni Idonda Nihonjin(Guidelines for treatment of hyperuricemia/gout)

Kagakushatachi (Japanese Scientists who Strove for(2012supplementary edition). Medical Review (2012).

New Medicine). Kodansha (2013).

Feigelson P., Davidson J. D. & Robins R. K.:[13] Enomoto A., Kimura H., Chairoungdua A., Endou H.

Pyrazolo-pyrimidines as inhibitors and substrates of

et al.: Molecular identification of a renal urate anion

xanthine oxidase. Journal of Biological Chemistryexchanger that regulates blood urate levels. Nature

226:993 (1957).

417: 447-52 (2002).

Rundles R. W., Metz E. N. & Silberman H. R.:
Allopurinol in the treatment of gout. Annals of Internal[14] Details on various products were made with reference
to the interview forms from the respective companies.

Medicine 64:229 (1966).
[9]

Iyakuhin Intabyū Fōmu (Drug interview form).
“Alositol®”. Mitsubishi Tanabe Pharma (revised 2008).

120

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

5

Conclusion/Acknowledgements

Drugs created through modern science have been of hugebenefit to humanity. Antibiotics and antibacterials haveachieved remarkable success in overcoming infectious
diseases, our greatest enemy since the dawn of humankind,
as well as in reducing infant mortality and significantly
extending our average life expectancy. This paper has
examined in detail how drug discovery has turned in focus
from fighting pathogens to addressing lifestyle-relateddiseases. The discussion has outlined how drugs withdifferent mechanisms of action have been adapted forpatients, for example, antihypertensives for hypertension
patients, such as beta-blockers, calcium channel blockers,
ACE inhibitors and angiotensin II receptor blockers. The
results are evident in the rapid decline in the cerebrovasculardisease mortality rate.
The discussion on diabetes drugs has examined thecompetition to create new drugs, such as pancreatic β-cellstimulants, insulin sensitizers, small intestine glucose
absorption inhibitors, incretin breakdown inhibitors andurinary glucose reuptake inhibitors, with successive researchand development of drugs with new mechanisms of action.
These drugs have significantly contributed to the treatment
of diabetes and it has been Japanese researchers who havemade outstanding achievements at the global forefront of the
field, discovering new drugs with new mechanisms of action,
including insulin sensitizers and urinary glucose reuptake
inhibitors.
Anticholesteremic HMG-CoA reductase inhibitors(statins) have had ground-breaking results in lowering the
mortality rate of patients with ischemic heart disease, thanks
to Japanese scientists. Japanese scientists also developed theidea of antiplatelets, developed hemostatics in the wake of
the Second World War and discovered antithrombins. Whilesome of these achievements have been by chance, theJapanese have also thought outside the box to come up withideas that other researchers did not and have had theresilience to surmount repeated failures, which has played
significant role in their success. May future generations ofresearchers draw from this.
As well as world-first innovative drugs, this paper has also
examined how Japanese drug discovery companies havediscovered many improved new drugs. While improved new
drugs are somewhat critically regarded as Japan’s forte, theability of medicinal chemists to produce drugs that are better
than preceding products at low cost and in a compact mannerby means of experience, intuition and luck simply
demonstrates their superior competence as researchers.
Major drug discovery companies in the West have similarly
produced and marketed improved new drugs, many of whichhave gained worldwide use. Since the aim of drug discovery
is to discover drugs that will contribute to humanity rather

than to be the first in the pack, it is worth far more to be bestin class than first in class. Japanese drug discovery has aunique history in that quite a number of companies, not all ofthem specialized, have cleverly maximized their limited
resources to create improved new drugs. Drug discovery in
the future will involve companies studying what has gone
before and developing new improved drug technologies, withconfidence in their conventional improved-drug-oriented
approach.
The history of modern drug development involves large
numbers of patients and progress in determining the causesof diseases. When examining diseases by their cause,
pathogens and viral infections are obvious targets. Stomach
ulcers have been brought under control by preventing
excessive secretion of gastric acid. Anti-inflammatories havebeen effective against inflammatory pain. The mechanismsof hypertension and hyperlipidemia have been determinedand effective new drugs have emerged. However, there arestill many cases of diseases without one simple cause, or
niche diseases; these will become the targets of new fields of
drugs in the future.
Nevertheless, current competition in the field of drug
discovery is not limited to these new areas. Even in fields
where the repertoire of drugs is near complete, there issometimes an ongoing quest to discover new blockbuster
drugs with new mechanisms of action. Is it truly necessary to
discover new drugs with new mechanisms of action or try tofind blockbuster drugs for diseases that are alreadyadequately treated with existing drugs? It does seemreasonable to consider ways to make existing drugs more
effective.
Aspirin is known and used all around the world as ananalgesic and antipyretic and is also a very good platelet
aggregation inhibitor. However, there are patients who areunresponsive to aspirin, while other patients suffer fromsevere side effects with even the slightest amount. The effectof the drug is made more accurate by identifying
aspirin-unresponsive patients through advance gene
expression testing and then administering accordingly. Whilesome endeavors have been made to that end, it is important
to use such means more widely in consideration of otherdrugs as well.
How effective are scientifically-created drugs in thismodern era? The efficacy of drugs is determined in clinicaldrug trials by measuring subjective or objective indicators
using double blind testing under GCP-compliant protocols.
With neither doctors nor patients knowing if is the drug or
the placebo being taken, such conditions should clearly
reveal whether the drug actually is effective. However, inmany cases, there is little discernible difference between thecontrol group and the treatment group. Table 5.1 reveals that
drug efficacy varies considerably between clinical trials(except for anti-pathogenic drugs). Even properly controlled

Systematized Survey on the History of Drug Discovery with Technical Development

121

clinical trials yield these results, indicating variations inefficacy on administration to ordinary patients after the drug
has gone to market.
Table 5.1 How Effective are Drugs?
DiseaseRheumatism
CancerDepression
Diabetes
Gastric ulcer
Duodenal ulcer
Hyperlipidemia
Hypertension
‫ײ‬
‫ײ‬
‫ײ‬
Migraine

Drug
NSAID COX-2 inhibitors
Various anti-cancer drugs
SSRI inhibitors
Sulfonylurea
Proton pump inhibitors

Efficacy
50-80%
0-30
60-80
50-70
10-80

Statins
Diuretics
β-blockers
ACE inhibitors
ARBs
Serotonin antagonists

25-70
25-50
70-80
70-90
70-90
50-75

Source: BM Silber, “Pharmacogenomics, Biomarkers, and the Promise of Personalized
Medicine,” Pharmacogenomics, W. Kalow and U. Meyer, editors, Marcel Dekker Publishers, New
York, 2001; Perlegen anlysis.

Placebos have been discussed in this paper, but there areother differences in environment and lifestyle. The othermajor cause of variation is thought to be due to individual
and racial differences between patients, rather than due to theinadequacy of the efficacy of the drug. There are some drugs
that have no effect on certain patients. The extent to which adrug is effective depends on differences in disease-related
gene expression in different patients, as well as differences indrug metabolism in different individuals.
The concept of personalized medicine is that of using
individual gene expression testing and biomarker testing topredict the effects and side effects when administering aparticular drug. The ideal treatment is that which uses the
optimal drugs for the individual, as also mentioned in thispaper. Research in this area has been ongoing since the endof the 20th century, with a view to integrating diagnosis anddrug administration in treatment. However, there is no easy
way forward. The more diagnostic methods and types ofdrugs there are, the higher the medical expenses are going to
be. This will also add to the load on doctors and othermedical personnel as well as increasing the cost of drug
manufacturing. Research has to begin with genetic diagnosis
to identify the optimal biomarkers. At this point, there are anumber of issues needing to be resolved, requiring close
collaboration and joint initiatives between thepharmaceutical industry and the diagnostic equipment
industry, the medical examination industry and university
researchers. However, this is a road that must be travelled. It
will require companies that have produced successful
products to get involved in increasing the efficacy andreducing the side effects of their products.
Active drug discovery research is continuing in fields inwhich there are no adequate drugs as yet. While one strategy
is to try to find a blockbuster drug in fields where solutions
can be achieved by extending past experience, there aremany diseases that have complex causes relating to manydifferent genes. While we are entering an age of genomic
drug discovery, many candidate genes are being discovered

122

that are potential causes for each disease. If there are over
100 candidate genes that could cause schizophrenia, it isdifficult to determine which gene is actually the cause.
Conversely, diseases are also thought to occur due to theinvolvement of multiple genes. Accordingly, the fact thatmultiple genes are involved in diseases in a complex manner
really implies that no perfect drug with one mechanism ofaction will be forthcoming.
These fields must be approached with new treatment ideasthat are distinct from conventional treatment. Drug discovery
also needs to be undertaken in line with such policies. The
correlation between the disease suffered by a patient and thatpatient’s genetic makeup in relation to that disease must be
clearly understood. This will require drugs with multiple
mechanisms of action as well as patient profiling. This is alsopart of personalized medicine.
There are various different cases to be considered inrelation to the future direction of drug discovery. The hope isthat Japanese drug discovery companies will clearlyrecognize their past achievements and move forward withnew concepts and creativity without getting stuck on theconventional methods of drug discovery.
How long can human life be extended?
The introduction of this paper stated that the average life
expectancy steadily increased from the Meiji Period onwards
and then rapidly increased after the Second World War. One
theory suggests that simply eliminating death from various
infectious diseases in infancy and childhood would
dramatically increase the average life expectancy inadulthood.
As there are no official death records dating prior to the
Meiji Period, no simple comparison can be made with thepost-Meiji era. However, according to Hida O Jiin Kako-chō
no Kenkyū (Study of the Death Records in Hida O Temple)(Note 1)
(1973), a work by Gifu doctor Keizo Suda, the average
age at death in that region between 1771 and 1870 was 28.7
years for males and 28.6 years for females, while the average
age at death among adults over the age of 21 years was 61.4
years for males and 60.3 years for females. Historian Shōji
Tachikawa found that the average age of death of notablepeople in Japanese history was 60.4 years during the Warring
States Period of the mid-15th to mid-16th century, 66 years
during the Edo Period of the 17th to 19th centuries and 60.6
years in the Meiji and Taisho Periods of the late 19th century
to early 20th century (Nihonjin no Byōreki, Chuko Shinsho,
62-67, 1988).
As the Edo Meiji and Periods seem to have lacked any
policies to use treatment to extend the lives of sick people,
the average life expectancy of adults would have been thehealthy life expectancy (Note 2). According to the 2014 editionof the Ministry of Health, Labour and Welfare white paper
Towards Achieving a Healthy and Long-Living Society, thehealthy life expectancy in 2010 was 70.4 years for males and73.6 years for females. Compared to Suda’s data, the healthy
life expectancy has only increased by 9 years for males and13.3 years for females in 143-243 years.

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchCrude drugclassification

Infection

None

Placebo effect

Anesthetics / sedatives /hypnotics / euphorics

Drug classification

Disease classification

Chemotherapeutic
drugs
Antibiotics

Central/peripheral
nerve drugs

Central/peripheral
nervesDigestive systemdrugs

Respiratory
systemAnalgesics / antispasmodics /antipyretics

Anti-inflammatories /
analgesics

Digestive system

Medicinal
effectCathartics / laxatives /
emetics / stomachics /antidiarrheals

Respiratory/allergy
drugs

Cardiac/renal
diseaseHypotensives

Cardiotonics
Hypertension

Diabetes drugs
Diabetes
None

Antihyperlipidemic
drugs

Hyperlipidemia

Coagulation/ fibrinolytic
system drugs

Endocrine system
Immune system
drugs

None
Immune system

Endocrine/urological/
osteoporosis drugs

CancerRegenerative
medicine

Anti-cancer drugs
Personalized
medicine

Source: Umezu 2014

Fig. 5.1 Progression from Crude Drugs to Modern Drugs
It would also seem that the lifestyle-related disease
medications mentioned earlier have had surprisingly little
effect. Up until the Meiji Period, essentially genetically
healthy people survived being eradicated by pathogens andhad a high probability of reaching adulthood or old age,while modern-day adults have reached adulthood protectedfrom infection and other diseases by the power of medicine.
Accordingly, a simple comparison does not work. However,
perhaps we are reaching the limits of how far drugs canincrease the healthy life expectancy.
A significant challenge for the future will be how toextend the healthy life expectancy for all people, genetic
differences aside. Although there are new drugs to prevent
arteriosclerosis and treat diabetes, these are not the only
diseases that threaten our day-to-day health. There are manyother diseases and factors that can put an end to a healthy life,
such as becoming bed-ridden with an accidental broken bone
as a result of weakened bones and muscles and deteriorated
senses, loss of quality of life due to constant pain, diseases
resulting from a poor immune system, loss of mental energy
and dementia. If a tissue or organ ceases to function properly,
this can affect other parts of the body as well, thus impairing
the functionality of the entire body. Extending the healthy
life expectancy requires a balance of physical and mental
ageing. This will not be achieved by drugs alone; it will
require a full arsenal combining medical treatment and healthmaintenance.
The goal is to extend the healthy life expectancy not justfor the genetically healthy, but for all people regardless ofgenetic differences. Although this will take some very
in-depth basic research and may seem out of reach, it is agoal that is worthwhile.
In this era of regenerative medicine becoming a reality,

there are still many areas of active drug discovery. The hopeis that armed with the knowledge of the drug discoveries
achieved by our forebears, we would not tread the same
paths they took to seek out new drugs, but rather take on new
concepts and incorporate collaborative, holistic treatmentthat spans areas outside of drugs as well in order to battle
against diseases and ageing and extend the healthy life
expectancy of humankind.
(Figure 5.1 outlines the flow of this paper. Crude drugs havebeen broadly categorized four ways according to disease;
lifestyle-related diseases have been examined as separate
topics in this paper.)
Note 1: Many Japanese people in the Edo period were theparishioners of temples, and the temples have records of their death
period.
Note 2: The healthy life expectancy refers to the life span that can be
expected for individuals that are not limited by health issues in their
day-to-day life.

Acknowledgements: Sincere thanks to all those who kindly
assisted with the provision of reference materials andinformation for this paper, particularly Toshiya Kondo,
Junichi Sakai and Ryozo Tajima of Daiichi Sankyo Co., Ltd.,
Kazumi Kobayashi of Takeda Pharmaceutical Co., Ltd.,
Toshiro Sakaki, Sumihiro Nomura, Toshihiro Yamamoto andShinichi Ishii of Mitsubishi Tanabe Pharma Corp., Ei
Yamada and Kunimiki Otsu of AnGes, Inc. and Tomohiro
Nigo of Sumitomo Dainippon Pharma Co., Ltd.
Sincere thanks also to all of the various company
personnel for generously providing company history
information.

Systematized Survey on the History of Drug Discovery with Technical Development

123Systematization Diagram of Drug Discovery Technology in Japan (market release history of main diabetes drugs by mechanism of action)

NPH insulin

Cartridge type

Sustained type

InsulinNobel Prize awarded to Banting
and Macleod for the discovery
of insulin

Protamine Zn insulin
Ultra-fast-acting type
Successful gene recombination by Itakura et al.
(USA)

2014:
Canagliflozin
Glucoseremoval

2006: Miglitol

1988: Reaven
Concept ofSyndrome-X

Glucosidase
inhibitors

Phenformin: lactic acidosis report

2010: Alogliptin

1994: Voglibose

Incretins

TZ: Issue withcarcinogenesis

1970: UGDP trial; increased deaths in
SU/BG administered group

Biguanides

TZ: Issue with heart disease
1997: Troglitazone released
1999: Pioglitazone
2000: Sale of troglitazone suspended

1971: Buformin
1954: Phenformin

UKPDS trial; SUdrugs reassessed

1999: Nateglinide

1957: Tolbutamide

Glinide (fourth-generation)

First-generation
sulfonylurea drugs

2011: Repaglinide
1984: Gliclazide

Second-generation
sulfonylurea drugs

Sensitizers

Thiazolidine (TZ)

Biguanides reassessed

Third-generation
sulfonylurea drugs

1971: Glibenclamide

Insulin secretion promotion

Mass production of insulin commences (USA)

2000: Glimepiride

Source: Umezu 2014124

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchSystematization Diagram of Drug Discovery Technology in Japan (market release history of main hypertension drugs by mechanism of action)

1953: FDA approval of reserpine

1972: Calcium channel blocker effect discovered

1995: Calcium channel blocker safety dispute

1958: FDA approval of diuretics

1973: Diltiazem released (Japan)
1967-70: VA study proves hypotension decreases stroke

1997: USA JNC-VI disproves carcinogenesis of calcium channel blockers

2014: β removed as
first-line (JSH)

2002: Cardiotoxicity of calcium channel blockers disproven
2004: Free choice of first-line treatment (JSH)
2009: α removed from guidelines (JSH)

1976: Diuretics made first-line treatment (USA)2007: Eplerenone

1985: Indapamide

1965: Frusemide

Diuretics

1961: Spironolactone

1983: Labetalol

Beta-blockers

α/β-blockers
β-blockers (first-generation)
1966: Propranolol

1976: Nifedipine

1989: Nivaldipine

First-generation calcium
channel blockers

Second-generation calcium
channel blockers

Calcium channel blockers

1990: Bisoprolol
β-blockers(second-generation)

1996: Aranidipine

1988: Nicardipine
2003: Azelnidipine

1993: Amlodipine

Third-generation calcium
channel blockers
1998: Perindopril

ACE

1983: Captopril
2007: Aliskiren

ACE inhibitors

Renin inhibitors
1998: Losartan
1999: Candesartan

ARBs (first-generation)

ARBs

The upper arrows indicate the approximate release year
in Japan of antihypertensives by pharmacologicaleffect. The lower arrows in bold indicate the generaltrends in prescription.

ARBs (second-generation)

Source: Umezu 2014
2002: Telmisartan

2012: Azilsartan
2008: Irbesartan

Systematized Survey on the History of Drug Discovery with Technical Development

125Systematization Diagram of Drug Discovery Technology in Japan (market release history of main hyperlipidemia drugs by mechanism of action)

1948: Framingham Study commences (USA)

1985: Goldstein and Brown awarded the Nobel Prize

1985: Ion exchange resin released (Japan)
1991: Second-generation fibrates released
1967: FDA approval of clofibrate
1973: CPPT study proves correlation between cholesterol and coronary artery disease (USA)

1957: Seven-country epidemiological study commences (USA)

1978: Statins effective in preliminary clinical trial (Japan)
1994: Statins improve death rate and heart disease rate in secondary prevention trial
1980: Development of mevastatin discontinued
1971: Nicomol

1984: Nisetrol

Niacin1994: Ethyl icosapentate (indications expanded)

1963: Dextran sulfate ester
1985: Cholestyramine

1974: Soysterol

1999: Cholebine

Absorption inhibitors

Ion exchange resins

Sterols

Fibrates(first-generation)

1991: Bezafibrate

1981: Clinofibrate

Fibrates(second-generation)

Fibrates

1969: Clofibrate

2007: Ezetimibe

Absorption inhibitors

1985: Probucol

1999: Fenofibrate

1970: Simfibrate
1987: Lovastatin (USA)

2000: Atorvastatin

Statins(first-generation)

The upper arrows indicate the approximate release year in Japan ofhyperlipidemia drugs by pharmacological effect. The lower arrows in boldindicate the general trends in prescription.
Source: Umezu 2014

126

Statins(second-generation)

2005: Rosuvastatin

1998: Fluvastatin

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

Statins

Statins(third-generation)

1989: Pravastatin

Systematization Diagram of Drug Discovery Technology in Japan (market release history of main blood-related drugs by mechanism of action)

Aspirin

1899: Aspirin released (Germany)
1985: FDA approval of aspirin for secondary prevention of heart attack (USA)1999: Efficacy of aspirin extended (Japan)(ischemic heart disease, cerebrovascular disease)

1988: Aspirin reported to inhibit acute
myocardial infarction (ISIS-2 trial)

1967: Platelet aggregation inhibition of aspirin confirmed

1990: Argatroban (injected)

1916: Heparin discovered (USA)2011: Dabigatran (oral)

Antithrombins

1962: Heparin discovered (Japan)

2011: Edoxaban (oral)

Anti FXa
1962: Warfarin

Anticoagulants

1962: Platelet aggregation measuring device invented

2007: Fondaparinux (injected)
2013: Apixaban (oral)
1988: Cilostazol

1960: Dipyridamole

ADP receptor inhibitors

1981: Ticlopidine

1988: Alprostadil

Prostaglandins

2006: Clopidogrel

2014:
Prasugrel

1999: Epoprostenol

Antiplatelets

c-AMP promoters

1992: Beraprost
1988: Ozagrel

Other

1993: Sarpogrelate

The upper arrows indicate the approximate release year inJapan of blood-related drugs by pharmacological effect. The
lower arrows in bold indicate the general trends inprescription.

1983: Urokinase

1991: Alteplase

T-PA

1998: Monteplase (genetically modified)Fibrinolytics

Urokinase

1999: Pamiteplase (genetically modified)
Source: Umezu 2014

Systematized Survey on the History of Drug Discovery with Technical Development

127

Pharmaceutical Industry Technology History Resources

Location Confirmed

No.
Item
Year
1 Experiment book and monthly 1973
report recording the isolationand purification of component
ML-236 from culture filtrate (theworld’s first HMG-CoA
reductase inhibitor)
2 Takadiastase vial
1908-1913

Manufacturer
Type of resource
Akia Endo
Notes

Status of resource
TUAT Nature andScience Museum

Location
Reason for selection
2-24-16 Nakachō,A record of the discovery of the world’s first
Koganei-shi, Tokyo HMG-CoA reductase inhibitor ML-236. This drug
formed the basis for many statins and saved many
patients from diseases caused by arteriosclerosis.

SankyoVial

1-2-58 Hiromachi,
Shinagawa-ku,Tokyo

A digestive system drug researched and developed
by Jokichi Takamine. The oldest domestic
pharmaceutical product vial in Japan.

3

SankyoVial and packaging

Dr. Jokichi Takamine
Memorial Room,
Daiichi Sankyo Co.,Ltd.
Dr. Jokichi Takamine
Memorial Room,
Daiichi Sankyo Co.,Ltd.

1-2-58 Hiromachi,
Shinagawa-ku,
Tokyo

Jokichi Takamine and Keizo Uenaka’s discovery ofadrenalin made into a pharmaceutical product.

128

Adrenaline chloride vial andpackaging

1920-1932

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchChronological Table of Drug Development (Antidiabetics)
Classification
Insulin secretagogues

Mechanism of Action Category
Sulfonylureas

firstgeneration

secondgeneration

Fast-acting insulin Secretagogues(Glinides)
Glucose removals

Glucose absorption inhibitors(Alpha-glucosidase inhibitors)
Glucose reuptake inhibitors (GLT-2
inhibitors)

Insulin sensitizers

Biguanides

Thiazolidines
Incretins

GLP-1 analogs (Incretins)
DPP-4 inhibitors

thirdgeneration(fourthgeneration)Yearreleased
1957
1959
1964
1965
1971

Tolbutamide
Chlorpropamide
Acetohexamide
Glyclopyramide
Glibenclamide

1984
2000

Gliclazide
Glimepiride

1999
2004
2011
1993
1994
2006
2014
2014
2014
2014
2014

Nateglinide
Mitiglinide
Repaglinide
Acarbose
Voglibose
MiglitolCanagliflozin
Ipragliflozin
Dapagliflozin
Luseogliflozin
Tofogliflozin

1954
1961
1971
1997
1999
2010
2013
2009
2010
2010
2010
2012
2012
2013

Phenformin
Metformin
BuforminTroglitazone
Pioglitazone
Liraglutide
Exenatide
Sitagliptin
Vildagliptin
Alogliptin
Linagliptin
Teneligliptin
Anagliptin
Saxagliptin

Generic nameResearched/developed by (Note 1)

Domestic
product

Discovered by Upjohn
Eli Lilly / Shionogi
Kyorin Pharmaceutical
Discovered by B. Mannheim, F. Hoechst /Developed by Chugai Pharmaceutical
Discovered by Servier / Dainippon Pharma
Sanofi Aventis
Ajinomoto
Kissei Pharmaceutical
Sumitomo Dainippon Pharma
Bayer
Takeda Pharmaceutical
Sanwa Kagaku
Mitsubishi Tanabe Pharma
Kotobuki Pharmaceutical & Astellas
AstraZeneca, BMS
Taisho Toyama Pharmaceutical
Chugai Pharmaceutical / Sanofi, Kowa &Chugai Pharmaceutical

Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes

Aron Laboratories
SankyoTakeda Pharmaceutical
Novo Nordisk
AstraZeneca
Merck
NovartisTakeda Pharmaceutical
Boehringer Ingelheim
Mitsubishi Tanabe Pharma
Sanwa Kagaku
Kyowa Hakko Kirin

Systematized Survey on the History of Drug Discovery with Technical Development

Yes
Yes

Yes
Yes
Yes
Yes

129

Chronological Table of Drug Development (Antihypertensives)
Classification
Diuretics

Mechanism of Action Category
Loop diuretics
Thiazides
Thiazide analogs

Potassium retaining
β-blockers(selective aldosterone inhibitor)
β1 non-selective

β1 selective

α1 + β blocking

α-blockers

130

firstgeneration

secondgenerationYear
released
1965
1959
1960
1975
1982
1985
1961
1962
2007
1966
1973
1974
1980
1981
1986
1988
1992
1981
1983
1984
1990
1993
1983
1985
1988
1993
1981
1985

Generic name
Furosemide
Hydrochlorothiazide
Trichloromethiazide
Mefruside
Tripamide
Indapamide
Spironolactone
Triamterene
Eplerenone
Propranolol
Pindolol
BufetrolIndenolol
Carteolol
Nadolol
Nipradilol
Tilisolol
Acebutolol
Metoprolol
Atenolol
Bisoprolol
Betaxolol
Labetalol
Arotinolol
Amosuralol
Carvedilol
Prazosin
Bunazosin

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.MarchResearched/developed by (Note 1)
HoechstMerck / Banyu
Schering-Plough / Shionogi
Bayer / Yoshitomi
Eisai
Servier (Fr.) / Kyoto & Sumitomo
G.D. Searle / Pfizer
SKF / Kyoto & Sumitomo
PfizerAstraZeneca
Novartis
Yoshitomi
Yamanouchi
OtsukaSquibb / Dainippon
Kowa
Nisshin / Tomiyama
AventisAstraZeneca
AstraZeneca
E Merck / Tanabe
Santelabo / Mitsubishi Kasei
GlaxoSmithKline
Sumitomo & Ono
Yamanouchi
Boehringer Mannheim / Daiichi
Pfizer
Eisai

Domestic
product

Yes
Yes
Yes
Yes
Yes

Yes
Yes

Yes

Chronological Table of Drug Development (Antihypertensives)
Classification
Calcium channel blockers

Mechanism of Action Category
Dihydropiridine

firstgeneration
secondgeneration

thirdgeneration
ACE inhibitors

Diltiazem
SH-type
COOH-type

Angiotensin 1 receptor inhibitors

firstgeneration
secondgeneration

firstgeneration
secondgeneration

Renin inhibitors

Year
released
1976
1988
1989
1990
1990
1990
1991
1992
1994
1995

Nifedipine
Nicardipine
Nilvadipine
Nisoldipine
Manidipine
Nitrendipine
Benidipine
Barnidipine
Efonidipine
Felodipine

1995
1996
1993
2003
1973
1983
1988
1986
1989
1990
1991
1993
1993
1994
1995
1996

Cilnidipine
Aranidipine
Amlodipine
Azelnidipine
Diltiazem
Captopril
Alacepril
Enalapril
DelaprilCilazapril
Lisinopril
Benazepril
Imidapril
Temocapril
Quinapril
Trandolapril

1998
1998
1999
2000
2002
2004
2008
2012
2007

Perindopril
Losartan
Candesartan
Valsartan
Telmisartan
Olmesartan
Irbesartan
Azilsartan
Aliskiren

Generic nameResearched/developed by (Note 1)
Bayer
Yamanouchi
Fujisawa
Bayer
Takeda Pharmaceutical
Bayer / Tanabe
Kyowa Hakko
Yamanouchi
Nissan Chemical / Zeria
Astra & Hässle / Chiba-Geigy Japan & Hoescht
Japan
Fujirebio & Ajinomoto
Maruko & Taiho
PfizerUbe / Daiichi Sankyo
TanabeSquibb / Sankyo
Dainippon
Merck / Banyu
Takeda Pharmaceutical
Eisai
Merck & ICI / AstraZeneca
Novartis
Tanabe / Nihon Schering
SankyoWarner-Lambert / Tanabe
Discovered by Hoescht / Hoescht Japan &Roussel Japan
Servier / Daiichi
Merck / Banyu
Takeda Pharmaceutical
Chiba-Geigy Japan
Boehringer Ingelheim Japan
SankyoSanofi / Dainippon Sumitomo
Takeda PharmaceuticalNovartis Pharma

Systematized Survey on the History of Drug Discovery with Technical Development

Domestic
product
Yes
Yes
Yes
Yes
Yes
Yes

Yes
Yes
Yes
Yes
Yes
Yes

Yes
Yes

Yes

Yes
Yes

131

Chronological Table of Drug Development (Hyperlipidemia Drugs)
Classification

Mechanism of Action Category

Natural products

NiacinProbucolAbsorption inhibitors

Ion exchange resins
Cholesterol absorption inhibitors

Fibratesfirst-generation

second-generation
Statins

first-generation (isolated from culture solution)

second-generation (semi-synthesized)

third-generation (fully synthesized)

132

Year
released
1963
1966
1974
1994
1971
1984
1985
1985
1999
1983
2007
1965
1970
1981
1991
1999
1987
(USA)
1989
1991
1998
2000
2003
2005

Generic nameResearched/developed by (Note 1)

Dextran sulfate ester
Tocopherol nicotinate
Soysterol
Ethyl icosapentate
Nicomol
Niceritrol
ProbucolCholestyramine
Cholebine
Melinamide
Ezetimibe
Clofibrate
Simfibrate
Clinofibrate
Bezafibrate
Fenofibrate
Mevastatin
Lovastatin

Kowa
Eisai
Ajinomoto & Morishita
Mochida / Dainippon
KyorinBofors / SKK
Dow Chemical
BMS
Mitsubishi Chemical
Sumitomo
MSD
Discovered by ICI / Sumitomo
Yoshitomi
Sumitomo
Boehringer Mannheim / Kissei
Discovered by Fournier / Grelan
Sankyo (development discontinued in 1980)
Merck (USA and elsewhere; not sold in Japan)

Pravastatin
Simvastatin
Fluvastatin
Atorvastatin
Pitavastatin
Rosuvastatin

SankyoMerck
Novartis Pharma
PfizerNissan Chemical & Kowa
Shionogi

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March

Domestic
product
Yes
Yes
Yes
Yes
Yes

Yes
Yes

Yes
Yes

Yes

Yes

Yes
Yes

Chronological Table of Drug Development (Circulatory System Drugs)
Classification
Hemostatics

Antiplatelets

Mechanism of Action Category
Plasmin inhibitors

1965

Tranexamic acid

COX I inhibitors

1900

Aspirin

PDE inhibitors

1960
1988
1988
1988
1992
1999
1988
1993
1998
1981
2006
2014
1962
1990
2011
2007
2011
2012
2013
2009

1983
1983

Dipyridamole
Cilostazol
Alprostadil
Limaprost alfadex
Beraprost
Epoprostenol
OzagrelSarpogrelate
EPA-E (eicosapentaenoic acid ester)
Ticlopidine
Clopidogrel
Prasugrel
Warfarin
Argatroban
Dabigatran
Fondaparinux
Edoxaban
Rivaroxaban
Apixaban
Thrombomodulin α (recombinant
modification)
Streptokinase
Urokinase (extracted and refined)
Urokinase (tissue culture)

1992
1991

Nasaruplase (tissue culture)
Alteplase (genetically modified)

1991
1996
1998
1999

Tisokinase (tissue culture)
Nateplase (genetically modified)Monteplase (genetically modified)Pamiteplase (genetically modified)

Prostaglandins

TXA2 synthase inhibitors
5HT2 antagonists
Eicosapentaenoic acid
ADP receptor antagonists

Anticoagulants

Vitamin K blockers
Antithrombin (injected)
Antithrombin (oral)
Anti-FXa (injected)
Anti-FXa (oral)

Thrombomodulin
Fibrinolytics (thrombolytics)

Year
Generic namereleased
1954 Aminocaproic acid

Bacterial fibrinolysis
Urokinaset-PA (natural)

t-PA, genetically modified (second-generation)

Researched/developed by (Note 1)
Hayashi Kenkyusho & Mitsubishi Chemical /Daiichi
Kobe University, Mitsubishi Chemical &Daiichi / Daiichi
Bayer (trademark registered; activity started by
MR in 1908)
Karl Thomae / Boehringer Ingelheim Japan
OtsukaGreen Cross & Taisho
Ono & Dainippon
Toray & Kaken
GSK
Ono & Kissei
Mitsubishi Chemical
Nissui & Mochida
Parcor / Daiichi
Sanofi Aventis
Ube / Sankyo

Domestic
product
Yes
Yes

Yes
Yes
Yes
Yes
Yes
Yes
Yes

Yes

Mitsubishi Chemical / Daiichi
Boehringer Ingelheim Japan
Discovered by Sanofi-Sante / GSK (developed)
Daiichi Sankyo
Bayer
BMS & Pfizer
Asahi Kasei Pharma

YesGreen Cross & Mochida
Abbott / Dainippon & Mitsubishi
Petrochemical
Green Cross
Genentech / Mitsubishi Chemical & Kyowa
Hakko
Asahi Kasei & Kowa
Mitsui Toatsu, Mitsui & Mochida
Eisai
Yamanouchi

Yes

Systematized Survey on the History of Drug Discovery with Technical Development

Yes

Yes

Yes

Yes
Yes
Yes
Yes

133

Chronological Table of Drug Development (Gout/Hyperuricemia Drugs)
Classification
Gout
Hyperuricemia

Gout

Mechanism of Action Category
Uricosurics

Primary tubular reabsorption
inhibitor
Secondary tubular
reabsorption inhibitor,
anti-inflammatory effectSecondary tubular
reabsorption inhibitor
Uric acid production Xanthine oxidase inhibitor
inhibitors
Xanthine oxidase inhibitor
Xanthine oxidase inhibitor
Gout-specificanti-inflammatory
Additional
Anti-inflammatory (expanded
indications for gout indications as gout drugs)
drugs
Corticosteroids

134

Year
Generic namereleased1956 Probenecid

Researched/developed by (Note 1)

Domestic
product

Developed by Kaken

1967

Bucolome

Gifu University, Gifu Pharmaceutical
University & Takeda / Takeda

1978

Benzbromarone

Discovered by Labaz (Fr.) / Torii

1968
2011
2013
1964

Allopurinol
Febuxostat
Topiroxostat
Colchicine

Wellcome
Teijin Pharma
Fuji

Yes

Yes
Yes

Indomethacin
Naproxen
Oxaprozin
Pranoprofen, etc.
omittedNote 1
Where (/) is indicated, the main companies engaged in researching the new drug are
given to the left of the (/).
Companies involved from clinical development onwards or mainly involved in clinicaldevelopment are given to the right of the (/).
Here, “discovered by” refers to new drug research. Joint research or joint development isindicated with (&).

National Museum of Nature and Science Survey Report of Systematization of Technology, Vol.22 2015.March