day in New York City in 1995, before protease inhibitors were introduced, and this death rate fell to seven per day on average after their introduction.
Nationwide, the Centers for Disease Control estimates that up to 40,000 new HIV infections still occur annually. Of the new AIDS cases, 35 percent occur from male-to-male sex, 24 percent from intravenous drug use, 13 percent from heterosexual contact, and the rest from unspecified causes. A breakdown by race and ethnic background shows that 45 percent of new AIDS cases occur in blacks, 33 percent in whites, 21 percent in Hispanics, and one percent in other groups.
Structure-based drug design principles led to the synthesis of many thousands of in vitro potent HIV protease inhibitors, compounds that inactivate the HIV protease, leading to the production of immature and uninfectious viral particles. Unfortunately, the bioavailability characteristics of these high molecular weight compounds, especially their rapid hepatic elimination from the circulation, made them unsuitable as drug candidates. Navia et al (1996) focused on the bioavailability issues, in historical resonance with the development of captopril, and of the topical carbonic anhydrase inhibitor dorzolamide HCL. The resulting HIV protease inhibitor, VX-478, combines biochemical potency and specificity with a clear synthetic path to compound scale-up. Its very favorable bioavailability profile in man follows from its lower molecular weight, its aqueous solubility, and its minimal peptidyl character.
Thaisrivongs et al (1996) found from a broad screening program that the 4-hydroxycoumarin phenprocoumon was identified as a lead template with HIV protease inhibitory activity. The crystal structure of phenprocoumon/HIV protease complex initiated a structure-based design effort that initially identified the 4-hydroxy-2-pyrone U-96988 as a first-generation clinical candidate for the potential treatment of HIV infe...