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Science art and drug discovery, a personal perspectiveScience, Art and Drug Discovery, A Personal Perspective
Simon F. Campbell, PhD FRS
Formerly Senior Vice President, WW Discovery, Pfizer Central Research
The pharmaceutical industry is under intense pressure to increase productivity, and drug discovery is undergoing a paradigm shift whereby the explosion in genome sciences and new technologies is being harnessed to produce innovative therapies within shorter time scales. However, while new targets and screening hits are being identified at unprecedented rates, innovative science is still rate limiting in transforming leads into drug candidates. Moreover, since the structures of many receptors and enzymes are unknown, successful drug discovery teams must blend scientific data with experience and intuition to develop robust hypotheses for drug-receptor interactions that guide rational design and synthesis. These challenges, together with two innovative solutions, will be illustrated with the research programmes that lead to amlodipine (Norvasc ) and sildenafil (Viagra ). At the start of our research programme that lead to amlodipine, a once-daily calcium antagonist for the treatment of angina and hypertension, there were over 90 published patents around the parent dihydropyridine ring system which posed a significant challenge to establishing a strong proprietary position. Moreover, all agents of the class suffered poor pharmacokinetics, and there were no clues on how these might be improved. However, rational medicinal chemistry led to a novel series of dihydropyridines with potent calcium antagonist activity that displayed high, and uniform bioavailability, and long plasma half-lives. After extensive pharmacological profiling, UK 48,340 (amlodipine) was selected for clinical development and subsequently received worldwide approval as Norvasc™ for the treatment of hypertension and angina. Norvasc is now the world’s leading antihypertensive agent, and is the fourth best selling drug in the world, where over 30 billion patient days of therapy have been achieved since launch Sildenafil, the first oral treatment for male erectile dysfunction, was the result of a research programme to block the action of PDE 5 and increase tissue levels of cGMP, even though the endogenous ligand that stimulated guanylate cyclase was unknown at the time. Starting from zaprinast, a weak and non-selective PDE 5 inhibitor, computer modelling guided rational medicinal chemistry to achieve significant increases in potency and selectivity within a novel series of pyrazalopyrimidines. Optimisation of SARs and pharmacokinetics led to UK 92480 (sildenafil) that was essentially devoid of cardiovascular activity in clinical trials. However, the emerging role of nitric oxide and cGMP in controlling blood flow in the penis suggested that sildenafil would have a beneficial effect on erectile dysfunction. This hypothesis was confirmed by extensive clinical trials in nearly 5000 patients and sildenafil was approved by the FDA in March 1998 for male erectile dysfunction. Viagra is now one of the most widely prescribed medicines, with more than 120 million prescriptions written by some 600,000 physicians for over 20 million men worldwide. These research programmes will be discussed from a personal perspective that will highlight the importance of multidisciplinary project teams, challenges that arose during discovery and development and some factors that influenced key decisions. Finally, some comments will be offered on therapeutic trends and drug discovery over the next decade, particularly the impact of genome sciences and new technologies.
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