BIS TERTIARY AMIDE INHIBITORS OF THE HIV-1 PROTEASE GENERATED VIA PROTEIN STRUCTURE-BASED ITERATIVE DESIGN

A series of potent nonpeptide inhibitors of the HIV protease have been identified. Using the structure of compound 3 bound to the HIV protea se, bis tertiary amide inhibitor 9 was designed and prepared. Compound 9 was found to be about 17 times more potent than 3, and the structur e of the protein-ligand complex of 9 revealed the inhibitor binds in a n inverted binding mode relative to 3. Examination of the protein-liga nd complex of 9 suggested several modifications in the P1 and P1' pock ets. Through these modifications it was possible to improve the activi ty of the inhibitors another 100-fold, highlighting the utility of cry stallographic feedback in inhibitor design. These compounds were found to have good antiviral activity in cell culture, were selective for t he HIV protease, and were orally available in three animal models.