l-739594 and tetrahydrofuran

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.

Topics: Amino Acid Sequence; Aspartic Acid; Binding Sites; Crystallography, X-Ray; Drug Design; Furans; HIV Protease; HIV Protease Inhibitors; HIV-1; Hydrogen Bonding; Ligands; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Structure; Optical Rotation; Stereoisomerism; Structure-Activity Relationship

Topics: Crystallography, X-Ray; Drug Design; Furans; HIV Protease; HIV Protease Inhibitors; HIV-1; Hydrogen Bonding; Isoquinolines; Models, Molecular; Molecular Structure; Quinolines; Saquinavir