Structure-activity relationship of small-sized HIV protease inhibitors containing allophenylnorstatine

We designed and synthesized a new class of peptidomimetic human immunodefic iency virus (HIV) protease inhibitors containing a unique unnatural amino a cid, allophenylnorstatine [Apns; (2S,3S)-3-amino-2-hydroxy-4-phenylbutyric acid], with a hydroxymethylcarbonyl (HMC) isostere as the active moiety. A systematic evaluation of structure-activity relationships for HIV protease inhibition, anti-HIV activities, and pharmacokinetic profiles has led to th e delineation of a set of structural charateristics that appear to afford a n orally available HN protease inhibitor. Optimum structures, exemplified b y 21f (JE-2147), incorporated 3-hydroxy-2-methylbenzoyl groups as the P2 li gand, (R)-5,5-dimethyl-1,3-thiazolidine-4-carbonyl (Dmt) residue at the P1' site, and 2-methylbenzylcarboxamide group as the P2' ligand. The present s tudy demonstrated that JE-2147 has potent antiviral activities in vitro and exhibits, good oral bioavailability and plasma pharmacokinetic profiles in two species of laboratory animals.