Future horizons in drug discovery research.

The current state of the pharmaceutical industry, with its lower than expected productivity as measured by FDA approvals, has been clearly documented elsewhere, as well as the corresponding effects upon limiting employment opportunities for medicinal chemists. With that context in mind, here is a long-term perspective on drug discovery research, out to 100 years in the future. Any such musings are by nature tenuous and speculative, as it is impossible to know what events will intervene that could dramatically change the very fabric of human society in the next 100 years, such as financial instabilities, conflicts, and weather-related events. On the other hand, predictions on events 100 years in the future will transcend the lifespan of all but a few of those now being born who are alive today, so there is no way to be definitively proven wrong by any who read this during my or their lifetimes. One way to project the future 100 years of biomedical research is to consider changes that have occurred in the century prior to the present time. Up until the passage of the first Pure Food and Drug Act in 1906, it was possible to sell morphine, cocaine, or heroin without them being labeled as such. Top-selling pharmaceutical agents 100 years ago contained heavy metals such as arsenic or mercury. Salvarsan was the leading drug in 1912, an arsenic-containing drug discovered by Ehlrich and Hata in 1909 and introduced into the market by Hoechst in 1910 for the treatment of syphilis. Salvarsan was thought to contain an As=As double bond but was shown in 2005 to be a mixture of cyclic 3- and 5-membered ring As–As single bond-containing species. The design process to obtain Salvarsan involved iterative medicinal chemistry optimizing efficacy and water solubility, a forerunner to the structure–activity relationship (SAR) development campaigns of the present day. The most successful drug of all time, and certainly of our time, is Lipitor, which is just now converted to generic status after having produced >$14 billion in sales. The discovery processes for Salvarsan and Lipitor were similar but only in the broad outlines of iterative SAR development, preclinical efficacy testing, and positive treatment outcomes in patients. The scope and scale of the two research programs are dramatically different. First, our focus now is on organic drug substances, as inorganics are generally relegated to cytotoxic anticancer drugs or contrast imaging agents. Although the time between initial preparation and commercialization of Salvarsan was ∼1.5 years, today, this transition will require 8–12 years. The much larger number of researchers, much greater cost involved, the extensive profiling required for regulatory approval, and advantages required relative to standard of care relative to an established formulary of already approved drugs have exponentially expanded and complicated the drug development process over the past century and rightfully so for the safety of patients. As Ehlrich pointed out from his own experience “the step from the laboratory to the patient’s bedside...is extraordinarily arduous and fraught with danger.” The pharmaceutical industry is currently in a classic industry consolidation phase, with high levels of generic substitution and niche targets such as relating to orphan indications capturing a greater fraction of the whole. The pharmaceutical industry today can be compared with the agricultural chemical industry of ∼15 years ago, and the steel industry of the 1960s–1970s. In such cases, the margin to be achieved by value-added intellectual contributions is diminished by generic substitutions by others elsewhere competing on price with equivalent or close to equivalent perceived quality. There will continue to be a need for new drugs for indications not presently adequately treated or to provide disease modification and not just symptomatic relief and to address drug resistance or genetically engineered bioterrorism among infectious diseases. Here is a short list of predictions for what drug discovery will look like 100 years in the future.