Structure-based drug design of nonpeptidic P2 substituents for HIV-1 protease inhibitors

Abstract The cocrystal structures of LY289612 and LY297135 were used as a starting point in the design of nonpeptidic HIV-1 protease inhibitors. This report details the discovery of a series of novel aromatic P 2 replacement groups. The 3-hydroxy-2-methyl benzoic acid group, discovered in AG1254, was incorporated into the hydroxyethyl amine series to produce the potent antiviral compound (LY309391/ AG1310).