Blockbuster

One of the famous fathers of modern drug discovery, Leo Stembach, discovered and developed diazepam, which under its trade name Valium, became the first blockbuster dmg with sales exceeding 1 billion per year. It is also accused of unleashing a culture of quasi-accepted drug use for semirecreational use in anxiety-ridden mainstream America. The problem isn t so much in the drug itself, but problems arose from its interaction with alcohol and through its induction and development of both tolerance and dependence. 

Despite its side effects, it is still the golden standard for anxiolytic activity. Dr. Stembach made such a good compound that this is the most robust and most fast acting anxiolytic, and efforts over the last 40 years have been to improve the therapeutic ratio by lowering the side-effects while retaining the efficacy. The many benzodiazepines are the mainstay anxiolytics. The modern antidepressants (Prozac, Paxil, etc.) were shown to act on anxiety, but these safer drugs are less robust than diazepam. 

Leo Stembach is also responsible for more than 100 patented compounds without benefit of high- throughput screening to assist him. Perhaps his main legacy is that he created the dream of all dmg companies with his blockbuster. They want a few products that are easy to market, and they should all sell a lot. 

The library can be vastly expanded because of a technical breakthrough. One no longer needs massive quantities of chemicals to test. With in silico screening one can test the theoretical fit of the compound to the target using three-dimensional computer models of both structures. 

Where does man insert himself back into the process Once the hit is detected, the molecule has to be checked for stability, acute toxicity, and possible drug interactions with commonly used other drugs. Various structural changes may then be introduced by some of the 1,000 medicinal chemists at the company. The pharmacokinetics and toxicology are then determined to create the clinical candidate, and, if one sensibly plans ahead, an alternative as backup is developed in parallel. 

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Uses. Minols have historically been used in four types of ordnance, a) underwater (mines, torpedoes and depth charges) where the confinement of water offsets some of the loss of detonation velocity, b) blockbuster bombs in which a sustained and powerful impulse is more destructive than a high peak press, c) concrete fragmentation bombs where the high impulse will impart a satisfactory fragment velocity but will not pulverize the concrete they contact on impact, and d) in general purpose (GP) bombs... 

During the course of this chapter we have described the changing environment that will eventually see the pharmaceutical industry producing a range of products and services far removed from the blockbusters of today. This poses significant challenges to these corporate behemoths. The avalanche of... 

The selection of functional molecules was oriented at targeting blockbuster syntheses for pharmaceutical companies [83]. In this way, an already marketed blockbuster synthesis was applied to micro flow processing, with the aim of finally achieving production in micro reactors for the same synthesis. 

Furan-containing molecules are found in both natural products and pharmaceuticals. At one time, furfural was produced in great quantities from corncobs. Perillene, a secondary plant metabolite, is an example of naturally occurring furans. Furan is frequently used as a bioisostere of a benzene ring in medicinal chemistry. For example, Ranitidine (Zantac) marketed by Glaxo was one of the first blockbuster drugs with annual sales over 1 billion dollars. 

This chapter describes the many approaches employed to identify and then develop new pharmaceuticals. This chapter has endeavored to outline the careful multidisciplinary tasks that must take place in a timely fashion to insure that the inherent power of each new drug candidate is allowed to be fulfilled. Since the first edition of this book was published, Big Pharma has become even bigger and the quest to regularly introduce blockbusters (products with sales in the billions) is even greater. This has resulted in the adoption of HTS tools in... 

Is the discovery and development of another blockbuster monoclonal antibody like rituximab a feasible research and development model today Many of the special events that contributed to its success are probably not replicable. As with several other successful drugs, the market turned out to be much larger than anticipated, so competition from other drugs being simultaneously developed was not so intense. Similarly, the ability to manufacture the drug in a cost-effective manner did not exist when the project was initiated, but there were other advantages unique to rituximab. Its toxicity is minimal, a... 

Lawrence S. BUhon dollar babies— biotech drugs as blockbusters, Nature Biotechnology 25 380-382 (2007). 

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