STRUCTURE-BASED DESIGN AND SYNTHESIS OF SUBSTITUTED 2-BUTANOLS AS NONPEPTIDIC INHIBITORS OF HIV PROTEASE - SECONDARY AMIDE SERIES

The design, synthesis, and crystallographic analysis of protein-inhibi tor complexes is described for a novel series of nonpeptidic HN protea se (HIV Pr) inhibitors. Beginning with a cocrystal structure of a Phe- Pro peptidomimetic bound to the HIV Pr, design was initiated that resu lted in the substituted 2-butanol compound 8 as the lead compound (K-i = 24.5 mu M, racemic mixture). Modifications on the initial compound were then made on the basis of its cocrystal structure with HIV Pr and inhibition data, resulting in compounds with enhanced potency against the enzyme (compound 18, K-i = 0.48 mu M). These inhibitors were foun d to bind to the enzyme essentially as predicted on the basis of the o riginal design hypothesis. Stereospecific synthesis of individual enan tiomers confirmed the prediction of a binding preference for the S alc ohol stereochemistry. Modest antiviral activity was demonstrated for s everal of the more potent HIV Pr inhibitors in a HIV-1 infected CEM-SS cell line.