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Science, art and drug discovery: a personal perspective
1Pfizer Central Research, Sandwich, Kent CT13 9NJ, UK.
Clinical Science (London, England : 1979)
|September 21, 2000
Summary
Sildenafil was developed as a cardiovascular drug but found success treating erectile dysfunction. This discovery highlights the importance of exploring unexpected therapeutic applications for novel compounds.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Drug Discovery
Background:
- The development of Sildenafil (Viagra) began in 1985.
- Initial research aimed to create phosphodiesterase inhibitors for cardiovascular conditions.
Purpose of the Study:
- To design and synthesize novel phosphodiesterase inhibitors.
- To identify compounds that increase cyclic guanosine monophosphate (cGMP) levels.
- To explore therapeutic applications beyond cardiovascular disease.
Main Methods:
- Utilized computer modeling and rational medicinal chemistry.
- Optimized pyrazolopyrimidinone derivatives, starting from zaprinast.
- Conducted structure-activity relationship and pharmacokinetic studies.
Main Results:
- Achieved significant potency and selectivity for the phosphodiesterase type 5 (PDE5) isoenzyme.
- Sildenafil showed minimal cardiovascular activity in clinical trials.
- Clinical trials confirmed efficacy for treating male erectile dysfunction in nearly 5000 patients.
Conclusions:
- Sildenafil was approved by the FDA in 1998 for erectile dysfunction.
- The drug's success underscores the role of nitric oxide and cGMP in penile blood flow.
- The research program demonstrates a shift towards integrating genomics and new technologies in drug discovery.
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