Nonpeptidic potent HIV-1 protease inhibitors : (4-hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl)thiomethanes that span P1-P2' subsites in a unique mode of active site binding

• Published in: Journal of medicinal chemistry 1995-03, Vol.38 (6), p.898-905
• Main Authors: VARA PRASAD, J. V. N, PARA, K. S, GRACHECK, S. J, BHAT, T. N, BEISHAN LIU, BALDWIN, E. T, ERICKSON, J. W, SAWYER, T. K, TUMMINO, P. J, FERGUSON, D, MCQUADE, T. J, LUNNEY, E. A, RAPUNDALO, S. T, BATLEY, B. L, HINGORANI, G, DOMAGALA, J. M
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Amino Acid Sequence; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Binding Sites; Binding, Competitive; Biological and medical sciences; Cells, Cultured; Crystallography, X-Ray; HIV Protease Inhibitors - chemical synthesis; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Kinetics; Medical sciences; Models, Molecular; Molecular Sequence Data; Molecular Structure; Pharmacology. Drug treatments; Pyrones - chemical synthesis; Pyrones - chemistry; Pyrones - pharmacology; Sensitivity and Specificity; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804

Using molecular modeling and the information derived from the X-ray crystal structure of HIV-1 protease (HIV PR) complexed with the pyran-2-one 1, a series of (4-hydroxy-6-phenyl-2-oxo-2H-pyran-3-yl)thiomethanes was designed and analyzed as novel, nonpeptidic inhibitors of HIV PR. Structure-activity studies led to the discovery of inhibitor 19 having (RS)-1-(cyclopentylthio)-3-methylbutyl functionalization at the C-3 position, which exhibited a Kc of 33 nM. A X-ray crystallographic structure of 19 bound to HIV PR showed that structural water-301 (inhibitor-flap-bridging water) was displaced by the inhibitor. Interestingly, the enol moiety of the pyran-2-one formed a hydrogen bond directly with Asp125 and with Asp25 via a bridging water molecule, thus illustrating a unique mode of active site binding by an HIV PR inhibitor. The pendant cyclopentyl and isobutyl groups of 19 occupied the S1' and S2' binding sites, respectively, whereas the 6-phenyl group occupied a region in between the S1 and S3 pockets of HIV PR. Selected compounds were tested for antiviral activity on H9 cells infected with HIV-1IIIb. A correlation between enzymatic activity and antiviral activity was not found in this series. The best antiviral compound in this series, 18, contained (RS)-3-[cyclopentyl(cyclopentylthio)methyl] functionalization at the C-3 position of the pyran-2-one ring and exhibited a CIC50 of 14 microM and TC50 of 70 microM. These studies demonstrate that potent enzyme inhibition can be achieved by inhibitors that span only three subsites.