STRUCTURE-BASED DESIGN OF NOVEL HIV PROTEASE INHIBITORS - CARBOXAMIDE-CONTAINING 4-HYDROXYCOUMARINS AND 4-HYDROXY-2-PYRONES AS POTENT NONPEPTIDIC INHIBITORS

The low oral bioavailability and rapid biliary excretion of peptide-de rived HIV protease inhibitors have limited their utility as potential therapeutic agents. Our broad screening program to discover nonpeptidi c HIV protease inhibitors had previously identified compound II (phenp rocoumon, K-i = 1 mu M) as a lead template. Crystal structures of HIV protease complexes containing the peptide-derived inhibitor I 4(R)-dih ydroxy-2(R)-isopropylhexanoyl-L-isoleucine N-(2-pyridylmethyl)amide) a nd nonpeptidic inhibitors, such as phenprocoumon (compound II), provid ed a rational basis for the structure-based design of more active anal ogues. This investigation reports on the important finding of a carbox amide functionality appropriately added to the 4-hydroxycoumarin and t he 4-hydroxy-2-pyrone templates which resulted in new promising series of nonpeptidic HIV protease inhibitors with improved enzyme-binding a ffinity. The most active diastereomer of the carboxamide-containing co mpound XXIV inhibited HIV-1 protease with a K-i value of 0.0014 mu M. This research provides a new design direction for the discovery of mor e potent HIV protease inhibitors as potential therapeutic agents for t he treatment of HN infection.