bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Multilateral Donor Non-System: Towards Accountability and Efficient Role Assignment
Authors: Reisen Helmut 
Published: September 2010

AbstractGlobal governance refers to several pillars; one important pillar is the multilateral aid architecture. Its reform can be discussed under the perspectives of representativeness, inclusiveness, and efficiency (of aid delivery). A prerequisite for efficient aid delivery is to map the rising complexity of multilateral development finance, to help identify areas for consolidation, address fragmentation and poor co-ordination at country level, and help identify comparative advantages for an institutional role assignment among multilateral agencies. After doing just that, the paper explores why the multilateral donors have proliferated and provides broad recommendations for a more efficient and accountable multilateral donor system.
History of Quantitative Structure–Activity Relationships
Authors: Selassie Cynthia , Verma Rajeshwar P. 
Published: September 2010

AbstractThis chapter gives an overview of the historical development of the quantitative structure–activity relationship (QSAR) paradigm with a particular emphasis on the past 50 years. Parameters used to formulate various mathematical models are described as originally delineated. Refinement and fine‐tuning of these variables as they evolved and were utilized, is also described. They are sequestered according to their electronic, hydrophobic, steric, and molecular orbital properties. Recent emphasis on molecular descriptors in high‐throughput screening mandates their inclusion in this chapter. Various QSAR models spanning two‐dimensional space to six‐dimensional space are described and applied to various chemicobiological systems in isolated receptors,in vitrosystems andin vivosystems. The presence of outliers in QSAR is also discussed in this chapter. Validation methods that are pertinent to QSAR model development are also addressed. The development of databases that encapsulate significant data on variables and models that allow for rapid retrieval, usage, and validation of chemical reactions and biological interactions is included in this analysis of QSAR.
Chirality and Biological Activity
Authors: Singh Jasbir , Hagen Timothy J. 
Published: September 2010

AbstractThe relationship between chirality and biological activity has been of increasing importance to the pharmaceutical and biopharmaceutical areas as evidenced by a growing number of chiral drugs that have been developed within the last two decades. This chapter covers several areas of importance in the design and synthesis of novel small molecule chiral drugs for medicinal chemists. The focus of this chapter is to provide an overview of the impact of chirality in medicinal chemistry and pharmaceutical sciences, and this should not be considered an exhaustive review of the topic. Several examples reported in the recent literature have been used to highlight the impact of chirality on development of therapeutics for various molecular targets. Chirality, as used in this chapter, also includes examples of atropisomers. The effects of chirality on pharmacological activities, absorption, distribution, metabolism, and excretion and toxicity are exemplified. In addition to chirality at carbon, examples of chiral compounds involving chirality at noncarbon atoms are included. A section on chirality in drug design provides several examples from recent literature covering diverse target classes. Regulatory considerations that apply to chiral drugs are addressed briefly. Section 10 covers recent drug development and marketed single enantiomers. Multiple synthetic approaches to produce chiral compounds with high enantiomeric purity, including chromatographic separation and enantioselective syntheses, were covered adequately in the 6th edition, and thus these areas and general definitions of chirality are not repeated in this chapter.
Principles of Drug Metabolism
Authors: Testa Bernard 
Published: September 2010

AbstractThe focus of this chapter is essentially on drug metabolism reactions and their enzymes. Connected information of significance to medicinal chemists is also given attention. Introductory principles of drug metabolism are presented in the introduction. Oxidoreductases are discussed in the next section together with a systematic and extensive treatment of the chemical groups they target and the functionalization reactions they catalyze. Attention is paid to the cytochromes P450, their multiplicity, specificities and relative importance. Hydrolases are also treated. The next section is dedicated to the transferases and the conjugation reactions they catalyze, for example, glucuronidation and glutathione conjugation. The last section, which is particularly close to the interests of medicinal chemists, discusses pharmacological and toxicological consequences of metabolism, structure‐metabolism relationships and the prediction of metabolism, and briefly outlines the biological factors that influence biotransformation.
Retrometabolism‐Based Drug Design and Targeting
Authors: Bodor Nicholas , Buchwald Peter 
Published: September 2010

AbstractRetrometabolic drug design (RMDD) approaches are systematic methodologies aimed to design safe compounds with an improved therapeutic index. RMDDs thoroughly integrate structure– activity and structure‐metabolism considerations into the entire design process and incorporate two major concepts aimed to design soft drugs and chemical delivery systems, respectively. Soft drugs (SDs) are new, active therapeutic agents designed to undergo predictable metabolism resulting in inactive metabolites after exerting their desired therapeutic effect(s). Chemical delivery systems (CDSs) are biologically inert molecules that provide enhanced and targeted delivery of an active drug to a particular organ or site through a designed sequential metabolism that involves several steps. Here, we present a comprehensive review including a general overview of the RMDD principles and a large number of specific examples from various pharmacological areas, including many recent developments, to illustrate RMDD concepts. Whenever possible, the rationale for the design as well as the pharmacokinetic and pharmacodynamic properties of the new therapeutic agents are briefly summarized and compared to those of the other compounds used in the same field.
Oxygen DeliveryviaAllosteric Effectors of Hemoglobin and Blood Substitutes
Authors: Bruno Stefano , Ronda Luca , Faggiano Serena , Bettati Stefano , Mozzarelli Andrea 
Published: September 2010

AbstractHemorrhages, disease‐ or genetics‐caused anemic conditions, and ischemic events prevent an adequate supply of oxygen to peripheral tissues. The most common therapy for these conditions is transfusion with whole blood from healthy donors. However, blood transfusions may suffer from side effects, potential shortages in donor availability, limited time storage, and applicability only within hospitals. Moreover, in cases such as immunoreactivity against all blood types, hypo‐oxygenation pathologies in preterm infants and refusal of transfusions on religious grounds, a blood substitute might be the only therapeutic option. In the past 30 years, several approaches have been pursued for the development of blood substitutes, based either on compounds capable to allosterically modulate the oxygen binding properties of endogenous hemoglobin or on artificial oxygen carriers directly administered in the blood stream. The latter are represented by oxygen‐solubilizing perfluorocarbons, chemically or genetically modified hemoglobins and artificial erythrocytes. Their successful development as safe alternatives to blood transfusions has been so far hampered by an incomplete understanding of the complex mechanisms controlling oxygen and NO homeostasis and hemodynamics. However, the knowledge accumulated in the past years brings hope for the development in the near future of effective and safe blood substitutes.
Selective Toxicity
Authors: Block John H. 
Published: September 2010

AbstractA drug can be considered toxic in that it replaces the natural ligand for a receptor. A goal in drug design is develop a molecule that is selective for a particular receptor located on a specific target organ or tissue. Therefore, an ideal biologically active molecule will produce a specific pharmacological response without causing adverse reactions. There are at least four ways to improve a drug's selectivity. These methodologies are based on the biochemistry of the disease or the biochemistry of the drug's receptor, unequal distribution of the drug, differences in the target cell's structure and the drug's stereochemical properties. Pharmacological classes differ in their ability to show selectivity. Cancer chemotherapeutic agents generally show poor selectivity whereas phosphodiesterase inhibitors can be selective for a specific enzyme isoform. Most bacterial antibiotics show excellent selective toxicity for bacteria with minimal serious adverse reactions experienced by the patient. In contrast, antiviral and antifungal drugs can produce untoward reactions in patients. Monoclonal antibodies exhibit excellent antigen–antibody specificity, but can disrupt the normal immune response. The nonsedating antihistamines distribute less to the central nervous system relative to the first generation of antihistamines. The initially inactive proton pump inhibitors readily distribute to an extracellular space with high acidity that converts them to the active drug. To improve patient acceptance, an important goal is to design the drug such that it be transported to the desired receptor and ignore other sites.
Anticonvulsants
Authors: Gitto Rosaria , Luca Laura De , Sarro Giovanbattista De 
Published: September 2010

AbstractThis chapter focuses on the chemical structures, the mechanism of action and the main structure–activity relationships of selected current and prospective anticonvulsant agents. Particular attention will be addressed to molecular targets involved in the mechanism of action of not only currently used drugs but also now being developed drugs. The pharmacokinetic and pharmacodynamic aspects of the most representative anticonvulsant agents will be also considered.
Design of Peptidomimetics
Authors: Perez Juan J. , Corcho Francesc J. , Rubio‐Martinez Jaime 
Published: September 2010

AbstractThe scope of the present report is to review the concept of peptidomimetic and provide examples of a few stories behind their discovery and design, taken from the literature. Emphasis is given on the process of design, stressing a hierarchical approach, where it is evidenced how the information about the necessary chemical moieties and their spatial arrangement is gathered stepwise. The necessary multidisciplinary approach required is also highlighted, where medicinal chemistry, biophysical, and computational methods are used together to design small‐molecule therapeutic agents. Finally, the general ideas developed are applied to a few examples taken from the literature, classified into three major categories of peptide–protein interactions that may be object of peptidomimetic design: enzyme inhibitors, G‐protein‐coupled receptors, and protein–protein interactions.
Provisional
BCS
Classification of the Leading Oral Drugs on the Global Market
Authors: Dahan Arik , Amidon Gordon L. 
Published: September 2010

Abstract

In the early 1990s, a collaborative research effort between academia and the U.S. Food and Drug Administration (FDA) was initiated to establish a database of human jejunal permeabilities based on a Biopharmaceutics Classification System (BCS). The BCS broadly allowed the prediction of human absorption, Fraction absorbed (
F
abs
) and the rate‐limiting step in the intestinal absorption process of drugs following oral administration. The BCS classified compounds into one of four biopharmaceutical classes according to water solubility and membrane permeability characteristics. Today, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development and regulation, and an extensive validation/discussion of the BCS is continuously published in the literature. BCS has been effectively implanted by drug regulatory agencies around the world, and widely practiced by the pharmaceutical industry. The aim of this chapter is to present the BCS and its scientific basis, to describe its impact on regulatory practice of oral drug products, and to access the BCS classification of the top drugs on the global market. Finally, current and future directions in BCS related extensions, and their impact on the pharmaceutical industry, will be discussed.
Salt Screening and Selection
Authors: Semin David J. , Jona Janan , Peterson Matthew L. , Zanon Roger 
Published: September 2010

Abstract
Salt screening and selection is a critical factor for the developability of an active pharmaceutical ingredient (API). The main benefit to screening, identifying, and selecting the optimal salt form early in the lifecycle is to improve the bioavailability of the compound while addressing its associated physicochemical, stability, and mechanical properties. The role of the scientist in the screening process involves the selection of the counterions and solvents and to bring valuable experience during the crystallization process. There are numerous manual and automated assisted strategies across the pharmaceutical industry for salt screening; however, determining crystalline salts that have a low potential for polymorphism is the common goal. The selection of the optimal salt not only improves the manufacturing and marketability of the drug product but also positions and protects the intellectual property of the product through composition of matter patents.
Enzymatic Assays for High‐Throughput Screening
Authors: Carettoni Daniele , Verwaerde Philippe 
Published: September 2010

AbstractHigh‐throughput screening (HTS) is a multidisciplinary approach to investigate in parallel the pharmacological properties of a large number of small molecules, with the aim of identifying target‐specific lead compounds to be progressed as bioactive probes or therapeutic drugs. The complex integration of chemistry, biology, automation, informatics, and medicinal chemistry has prompted the evolution of HTS as an autonomous discipline integrated in the drug discovery process. Thus, HTS assays are differentiated from traditional laboratory assays by the requirement of extensive assay development and by the strict quality criteria that must be fulfilled to approach a screening campaign. In this perspective, biochemistry and enzymology have provided an essential support for the design and configuration of functional HTS assays for enzymatic targets. In turn, the impressive technological improvements of HTS have made available an unprecedented array of novel methods and instrumentations that have contributed to advance the biochemical and kinetic characterization of enzymes. In this chapter, the paradigms for the configuration of enzymatic assays for HTS are reviewed, emphasizing the tight interdependence between type and quality of the HTS assay and the outcome of a screening campaign. The sequential steps of assay development for HTS are examined, providing examples of alternative approaches to configure the activity of enzyme drug targets as HTS‐compatible assays.
Current and Emerging Therapies in Chronic Obstructive Pulmonary Disease
Authors: Montana John G. , Dyke Hazel J. , Craig Fox J. , Ray Nicholas C. 
Published: September 2010

AbstractChronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that is a leading cause of morbidity and mortality worldwide with an overall prevalence in adults >40 years estimated at 9–10%. The World Health Organization (WHO) estimates that, by 2020, COPD will be the third leading cause of mortality and the fifth leading cause of morbidity in the world. This smoking‐related disease is characterized by progressive airway obstruction that, unlike asthma, is relatively insensitive to bronchodilators and to the classic anti‐inflammatory therapy, corticosteroids. Current therapy focuses mainly on reducing symptoms using inhaled short‐acting and long‐acting bronchodilators either as monotherapies or in combination with inhaled corticosteroids. During the last decade, the pharmaceutical industry has focused on treating COPD distinctly from asthma but no novel agents that target the disease itself have been launched as therapies for this disease. As our understanding of the pathology of COPD has increased it has been established that the progressive pulmonary inflammation that is associated with COPD relates to disease severity. Thus, it is anticipated that drugs that reduce pulmonary inflammation will provide effective, disease‐modifying therapies. Here, we consider the potential of anti‐inflammatory drugs that are currently in clinical development for COPD and discuss how these might reduce pulmonary inflammation in this disease.
Medicinal Chemistry and Therapeutic Applications of the GasotransmittersNO,CO, andH2Sand their Prodrugs
Authors: Szabo Csaba 
Published: September 2010

AbstractNitric oxide(NO),carbon monoxide(CO), andhydrogen sulfide(H2S) are the main endogenous gasotransmitters. These gases are produced by the body by enzymatic reactions and serve physiological regulatory purposes including vasodilatation and anti‐inflammatory effects. Over the past decades, multiple approaches have been identified for the therapeutic exploitation of these three gasotransmitters, based on inhalation of the gases and/or the parenteral or enteral administration of various formulations of these molecules or their prodrugs. Here we overview the medicinal chemistry and the therapeutic applications of NO, CO, and H2S and their prodrugs. Inhaled NO is used clinically to selectively dilate the pulmonary vasculature in the therapy of the primary pulmonary hypertension of the newborn. Organic nitrates such as glyceryl trinitrate or nitroglycerin are used in the therapy of acute and chronic angina. Sodium nitroprusside is used to counteract acute hypertensive crisis. Another class of clinical‐stage NO donor drugs is the sydnonimines (molsidomine, linsidomine). Additional classes of NO donors include diazeniumdiolates (NONOates) andS‐nitrosothiols, with beneficial effects in various preclinical models of disease. With respect to CO, the main therapeutic approaches are CO inhalation (currently in clinical trials for the experimental therapy of delayed graft function associated with kidney transplantation) and carbon monoxide releasing compounds of various classes (in preclinical stage). With respect to H2S, a parenteral injectable formulation of the gas is currently is Phase I trials. Several classes of H2S donor molecules have also been identified, which are used in preclinical studies.
Dipeptidyl Peptidase 4 Inhibitors
Authors: Weber Ann E. , Thornberry Nancy A. 
Published: September 2010

AbstractDefective insulin secretion is a hallmark of type 2 diabetes (T2DM), and agents that increase the concentration of circulating insulin have proven beneficial in the treatment of diabetes. Dipeptidyl peptidase 4 (DPP‐4) inhibitors are a new oral approach to T2DM that lower glucose via stabilization of the incretin hormone glucagon‐like peptide 1 (GLP‐1), which has clearly established roles in insulin secretion and inhibition of glucagon production. These agents have been shown to produce clinically meaningful glucose control in a range of patients with type 2 diabetes without many of the liabilities that are associated with other oral therapies, including weight gain, edema, GI intolerability, and hypoglycemia. Accordingly, DPP‐4 inhibitors have excellent potential for use in both monotherapy and combination with established agents. Extensive structure–activity relationship (SAR) studies in many different laboratories have resulted in the identification of a number of clinical candidates. The most advanced of these have recently been approved for the treatment of T2DM, representing the first new oral therapy for treatment of this disease since the introduction of troglitazone in 1998.
Osteoporosis Therapy: Mechanistic Antiresorptives
Authors: Dodge Jeffrey A. , Bryant Henry U. 
Published: September 2010

AbstractOsteoporosis is defined as the thinning of bone resulting from the imbalance between bone resorption and bone formation, the two cellular mechanisms that regulate the remodeling of skeletal tissue. This loss of bone ultimately results in an increased risk of fracture. One therapeutic approach to treating patients with osteoporosis is to inhibit the process of bone resorption. This has been clinically manifested by the development of a number of large and small molecules that include calcitonin, integrin inhibitors, cathepsin K inhibitors, OPG/RANKL inhibitors, bisphosponates, and SERMS. This chapter describes recent advances in the anti‐resorptive field with a focus on clinically validated targets and the molecules that have been developed to regulate these pathways.
Proteasome Inhibitors
Authors: Wehenkel Marie , Kim Kyung Bo 
Published: September 2010

Abstract
The proteasome has emerged as a major player in regulating essential cellular activities such as cell proliferation and inflammation. The FDA approval of bortezomib, the first‐in‐class proteasome inhibitor drug, for treatment of recurring multiple myeloma, has validated the proteasome as a target for treatment of cancer. This has catalyzed intense medicinal chemistry and library screening efforts to develop novel or improved proteasome inhibitors. Currently, a number of proteasome inhibitors are being investigated in clinical trials for cancer therapy. In this section, particular attention is focused on these inhibitors under clinical trials as well as traditional medicine recently identified as proteasome inhibitors. In addition, we discuss some of the medicinal chemistry efforts in the course of development of proteasome inhibitors with better efficacy. Finally, we describe novel proteasome inhibitors that target specific subunits of proteasomes.
Opioid Receptor Ligands
Authors: McCurdy Christopher R. , Prisinzano Thomas E. 
Published: September 2010

AbstractOpioid agonists, exemplified by morphine, have been the most prescribed class of drugs for the management of moderate to severe pain for many years. These drugs have significant liabilities of addiction and constipation over long‐term use and acute overdoses can result in respiratory depression. For over thousands of years, opium and opium‐derived drugs have nonetheless been utilized for their therapeutic and recreational benefits. Due to their liabilities, medicinal chemists and clinicians have worked for years to discover novel agents or treatment courses that would be devoid of these side effects. Still to this day, there are no agents that meet these criteria. Therefore, efforts continue vigorously in the quest for drugs with potent analgesic effects without abuse or side‐effect potential. Many chemical classes have been sought after in this quest and the range from peptides to synthetic compounds to natural products. Morphine offered a template that was rigid and able to provide an enormous amount of structure–function relationships that many of the market analgesics are based on. To complicate matters, the endogenous opioid system is comprised of four distinct receptor subtypes. These receptors are all members of the G‐protein superfamily and are designated as mu (μ, MOP), delta (δ, DOP), kappa (κ, KOP), and nociception (ORL1, NOP). It has been realized over the years that a combination of activities at these receptors may result in agents that could be devoid of liabilities. Intensive efforts have been directed at improved probes for each receptor subtype and combinations of agonists and antagonists for combinations of these receptors. This review will discuss the structure–activity relationships, as they are currently understood, with regard to each of the major classes of compounds that interact with these protein targets.