The integration of medicinal chemistry, drug metabolism, and pharmaceutical research and development in drug discovery and development. The story of Crixivan, an HIV protease inhibitor.

Abstract

History tells us that when given a reasonably active lead compound, medicinal chemists usually are able to increase the potency of the lead structure to a useful degree. The critical challenge for developing a clinically useful therapeutic agent is to improve oral bioavailability of the compounds to a practical level. Despite a wide variety of structural modifications to an early HIV-1 protease inhibitor lead, no general solution has emerged for the poor bioavailability that is characteristic of this molecular class. However, we have developed a series of potent inhibitors with increased polarity incorporated into the inhibitor backbone that led to an increase in aqueous solubility without compromising potency. Pharmacokinetic studies in dog showed an improvement in bioavailability from less than 5% for most previous inhibitors to greater than 20% for an initial analogue. Further development of this series led to the discovery of Crixivan®, which has now gained widespread use in the treatment of AIDS.