Potent cyclic urea HIV protease inhibitors with benzofused heterocycles as P2/P2′ groups

Abstract

A series of benzofused heterocycles was examined to replace the metabolically unstable benzyl alcohol P2/P2′ groups of DMP 323 ( 1). Extremely potent inhibitors of HIV protease (Ki < 0.01 nM) and excellent antiviral activity (IC 90 = 8 nM) were found. An X-ray crystal structure of benzimidazolone 5a bound to HIV protease showed H-bonds to Asp30 and a bridging water molecule to Gly48.