POTENT AND SELECTIVE INHIBITORS OF HUMAN-IMMUNODEFICIENCY-VIRUS PROTEASE STRUCTURALLY RELATED TO L-694,746

A series of human immunodeficiency virus (HIV) protease inhibitors, wh ich are analogues of tyloxycarbonyl)amino]-4(S)-hydroxy-6-phenyl-2-(R) - [[4-(carboxymethoxy)phenyl]methyl]hexanamide (L-694,746), a metaboli te of the anti-HIV agent L-689,502, were synthesized. In these compoun ds, the acetic group linked to the para position of the P-1' phenyl in the reference inhibitor was replaced either by the bioisosteric phosp honomethoxy group and its diisopropyl/dibenzyl derivatives, or the 1 H -tetrazol-5-yl-methoxy group and its 1-benzyl derivative. In enzyme as says, phosphonomethoxy and tetrazolmethoxy analogues proved to be pote nt inhibitors of the HIV-1 protease, with IC50 values as low as 0.04 n M. When tested for anti-HIV-1 activity in cell-based assays, most of t he new derivatives proved active, with benzyl derivatives being more a ctive than their highly polar, unsubstituted counterparts. The dibenzy lphosphonomethoxy analogue was the most active compound, with an EC50 value of 10 nM and a selectivity index of 20 000. When compounds were examined for their capability to reduce p24 levels in both acutely and chronically infected MT-4 and H9/IIIB cells, all of them were found t o be active at concentrations close to those capable of preventing HIV -1-induced cytopathic effect.