Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
Basic Information
ID: ALA1129277
Journal: J Med Chem
Title: Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation.
Authors: Ghosh AK, Kincaid JF, Walters DE, Chen Y, Chaudhuri NC, Thompson WJ, Culberson C, Fitzgerald PM, Lee HY, McKee SP, Munson PM, Duong TT, Darke PL, Zugay JA, Schleif WA, Axel MG, Lin J, Huff JR.
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 10 pi-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.
CiteXplore: 8765511
DOI: 10.1021/jm960128k
Patent ID: ┄