Stories of Drug Developments

This chapter is not meant to provide a systematic discussion of drug developments, but merely gives a few interesting stories of how drugs were discovered and have been developed. A lot of complicated chemical formulas/stmctures are presented in this chapter, but you should not be worried about whether you understand them. It turns out that the drug function often depends not on the detailed structure but on the overall shape of the compound. Hence, you can look at it as a sort of picture with some shape, and that is sufficient to understand why drugs work and how it might be modified. 

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Gale, E.A.M. (2001) Lessons from the glitazones a story of drug development. Lancet, 357, 1870-1875. 

Funk C, Ponelle C, Scheuermann G, Pantze M (2001) Cholestatic potential of troglitazone as a possible factor contributing to troglitazone-induced hepatotoxicity in vivo and in vitro interaction at the canalicular bile salt export pump (Bsep) in the rat. Mot Pharmacol 59 627-635 Gale FA (2001) Lessons from the glitazones a story of drug development Lancet 357 1870-1875... 

Sources. (1) PhRMA (Pharmaceutical Research and Manufacturers of America) Press Release dated November 14, 2006. http //www.who.int/mediacentre/factsheets/fs310/en/ index.html [accessed April 19, 2007], (2) CNN.com. Largest Passenger Jet Unveiled, January 18,2005. http //www.cnn.eom/2005/BUSINESS/01/18/airbus.380/ [accessed April 19, 2007], (3) Tufts Center for the Study of Drug Development, http //www.bizjournals.com/ sanfrancisco/stories/2006/12/04/newscolumn3.html [accessed September 26,2007]. 

The development of the natural constituents of Podophyllum Resin into effective semisynthetic and, ultimately, totally synthetic compounds for the treatment of various kinds of cancer provides one of the most sustained and intriguing stories of drug discovery (92, 93). 

The first drug developed for widespread use was aspirin, today s most common pain reliever. Americans alone consume approximately 80 billion tablets of aspirin a year The story of the development of this modern pain reliever goes back more than 2,000 years In 400 b.c.e., the Greek physician Hippocrates recommended chewing bark of the willow tree to alleviate the pain of childbirth and to treat eye infections. 

Anyone who has worked for some time in the pharmaceutical industry has a story of how a successful drug was developed after a fortuitous coffee machine encounter between two or more scientists, or how a problem was not discovered until late-stage development because an important piece of information was missed. 

In many ways, the story of the discovery of aspirin is typical for the way in which new drugs are invented and developed in pharmaceutical research laboratories, where many individuals have to make a contribution and where it is often difficult to fathom completely what thought processes, suggestions and interactions lead to a successful new drug. 

The two key elements of any biotech story are the importance of the medical need and the rationale for why this idea is likely to work when previous efforts have failed. While the time value of money should theoretically be important, given the long timelines for drug development, in practice estimates of successful drug valuations and technical risks usually overshadow the risk-free time cost of money. 

Most researchers and drug companies, however, still appear to he conhdent that combinatorial chemistry holds untold promise for the future. Though they often admit that there is little to show hy way of approved products that have evolved from combinatorial techniques, they point out that the early years of new technologies are often marked by similar stories of limited success. Eventually, they say, comhinatorial chemistry will take its place with natural products, trial and error, serendipity, and other traditional roads to drug development as an essential tool in the design and production of new pharmaceutical products. 

The development of the benzodiazepine class of drugs for the treatment of a variety of neurological indications has proven to be an outstanting success story in the field of chemotherapy. However, these compounds often produce undesirable side effects when used as anti-anxiety or hypnotic agents. These side effects include sedation, physical dependence, amnesia, muscle relaxation, and ethanol potentiation. The development of a benzodiazepine receptor-based anxiolytic agent devoid of these side effects would constitute a major advance in the field and has been the focus of significant research efforts [284]. 

This book tells the story of the ubiquitin system as we currently know it from the regulation of basic cellular processes to quality control and the pathogenetic mechanisms of disease, from X-ray crystallography of the 26S proteasome to the interaction between substrates and their ligases, to the development of mechanism-based drugs, and to target-specific aberrant processes. 

Formidable chemical obstacles stood in the way of clinical development of these agents derived from natural products, notably in formulation of very poorly soluble compounds for intravenous infusion and in manufacture of bulk drug. For a time, production of Taxol from the bark of the Pacific Yew tree aroused public controversy, which became a story of nature and politics in pursuit of an anti-cancer drug [22]. 

There are several books on the history of the development of taxol, which is one of the most remarkable stories in product development. In fact, it inspired the 1992 motion picture Medicine Man, starring Sean Connery as a research botanist looking for a cancer cure in the Brazilian rain forest. For a time, it became a moral drama pitting the needs of patients of intractable ovarian and breast cancer against the passions of environmentalists to preserve an obscure Pacific yew tree. Suffness and Wall are two of the principals in this story, and they wrote (1995) It [Taxol] is not an obvious winner till the very end, and there were a number of times till the very end when it seemed highly likely that it would not be put into development at all, or that once it had been accepted, it would be dropped. More than 30 years passed between the discovery of taxol, with its potential as an anticancer drug, and its approval by the Food and Drug Administration (FDA) for clinical use. 

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