Nonpeptidal P2 Ligands for HIV Protease Inhibitors: Structure-Based Design, Synthesis, and Biological Evaluation

Abstract

Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease−inhibitor complex 1 led to replacement of two amide bonds and a 10π-aromatic system of Ro 31-8959 class of HIV protease inhibitors. Detailed structure−activity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particular interest, compound 49 with (3S,3aS,6aS)-bis-Thf is the most potent inhibitor (IC₅₀ value 1.8 ± 0.2 nM; CIC₉₅ value 46 ± 4 nM) in this series. The X-ray structure of protein−inhibitor complex 49 has provided insight into the ligand-binding site interactions. As it turned out, both oxygens in the bis-Thf ligands are involved in hydrogen-bonding interactions with Asp 29 and Asp 30 NH present in the S₂ subsite of HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.