NONPEPTIDAL P-2 LIGANDS FOR HIV PROTEASE INHIBITORS - STRUCTURE-BASEDDESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION

Design and synthesis of nonpeptidal bis-tetrahydrofuran ligands based upon the X-ray crystal structure of the HIV-1 protease-inhibitor compl ex 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-ac tivity studies have now established that the position of ring oxygens, ring size, and stereochemistry are all crucial to potency. Of particu lar 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 thi s series. The X-ray structure of protein-inhibitor complex 49 has prov ided insight into the ligand-binding site interactions. As it turned o ut, both oxygens in the bis-Thf ligands are involved in hydrogen-bondi ng interactions with Asp 29 and Asp 30 NH present in the S-2 subsite o f HIV-1 protease. Stereoselective routes have been developed to obtain these novel ligands in optically pure form.