Modern drug discovery is a difficult, arduous process, filled with enormous risk. Success, however, can provide relief of human suffering and increased longevity, worthy goals by any standard. Because the discovery and development of new pharmaceuticals is so difficult, application of the best management techniques to the process is essential. The story behind Celebrex[R] (celecoxib), a highly successful pain reliever and anti-inflammatory medicine used in the treatment of arthritis, illustrates many of these management tools and principles very well.
For more than 100 years, salicylates have been used to relieve pain and inflammation. Unfortunately, the naturally occurring compound, salicylic acid, has severe gastrointestinal and other side effects. Over 100 years ago, a Bayer chemist synthesized the acetylated derivative of salicylate, to obtain a compound, aspirin, with fewer side effects. Seventy-five years after the synthesis of aspirin, John Vane showed that the drug acted by decreasing the synthesis of inflammation-promoting prostaglandins, which are produced in the body through the action of an enzyme called cyclooxygenase. In time, a whole class of pharmaceuticals called non-steroidal anti-inflammatory drugs (NSAIDs) was developed, including ibuprofen and naproxen. These acted mechanistically like aspirin but had improved pharmacological profiles with fewer side effects. By the mid-1980s, there were at least 22 NSAIDs being sold on the global pharmaceutical market.
While traditional NSAIDs were certainly an improvement over high-dose aspirin therapy for the treatment of arthritis, they still retained some serious side-effects. Because prostaglandins are involved in the protection of the gastrointestinal tract from hydrochloric acid and are also involved in blood clotting, NSAID's tend to cause gastrointestinal bleeding as a severe side effect. In fact, in the United States alone in 1998, there were at least 120,000 hospitalizations per year resulting from NSAID-induced complications, and perhaps more than 16,000 deaths.
It was against this historical backdrop that in the mid-1970s my colleagues and I at Washington University in St. Louis became interested in the biology of inflammation. The experimental system that we chose to study was perfused rabbit kidney, which, as a model for inflammation, had the great advantage of having a built-in contralateral control (the kidney on the opposite side). It turned out that inflamed kidney produced large quantities of prostaglandin-like substance, which was reduced to zero by the concomitant application of aspirin. Follow-up work over the course of several years led to the hypothesis in 1988 that there were really two forms of cyclooxygenase in the body. One form, dubbed COX-1, was apparently a "house-keeping" or constitutive enzyme, found in many tissue types and responsible for the steady synthesis of those prostaglandins involved in the protection of the gastrointestinal tract and in blood clotting. The other form of the enzyme, imaginatively named COX-2, appeared to be inducible, that is, its level was dramatically increased at sites of inflammation.
In 1989, I joined the Monsanto Company to become chief scientist and later head of R&D of Monsanto's pharmaceutical subsidiary, Searle. (Monsanto and Searle merged in 2000 with Pharmacia & Upjohn to create a new company called Pharmacia.) Not surprisingly, I found industrial research and development to be different from science in academia. In academic science, the "product" is the discovery of new things about Nature. In industry, the product is something useful for unmet medical needs and with commercial value. This is a much riskier enterprise.
Target Selection Takes "Taste"
One of the greatest challenges facing a head of R&D in a drug company is the selection of targets. Today, the disciplines of molecular biology, analytical chemistry, synthetic organic chemistry, genomics, and computational biology provide unprecedented and powerful tools. …