Structure-based design and synthesis of substituted 2-butanols as nonpeptidic inhibitors of HIV protease: Secondary amide series

Journal of Medicinal Chemistry

Volumn 39, Issue 14, 1996, Pages 2781-2794

  Reich, Siegfried H ^a   Melnick, Michael ^a   Pino, Mark J ^a   Fuhry, Mary Ann M ^a   Trippe, Anthony J ^a   Appelt, Krzysztof ^a   Davies II, Jay F ^a   Wu, Bor Wen ^a   Musick, Linda ^a  

^a AGOURON PHARMACEUTICALS INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMIDE; BUTANOL;

ARTICLE; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; ENZYME ACTIVITY; ENZYME INHIBITION; HUMAN IMMUNODEFICIENCY VIRUS; HYPOTHESIS; PREDICTION; PROTEIN ANALYSIS; RACEMIC MIXTURE; RNA VIRUS; STRUCTURE ACTIVITY RELATION;

AMIDES; ANTIVIRAL AGENTS; BUTANOLS; CELL LINE; CRYSTALLOGRAPHY, X-RAY; DRUG DESIGN; HIV PROTEASE INHIBITORS; HIV-1; HUMANS; MODELS, MOLECULAR; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0030013628     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960093o     Document Type: Article

References (13)

1. Darke, P. L.; Huff, J. R. In HIV Protease as an Inhibitor Target for the Treatment of Aids. In Advances in Pharmacology; August, J. T., Ander, M. W., Murad, F., Eds.: Academic Press: San Diego, 1994; Vol. 25, pp 399-454 and references cited therein.
2. Thaisrivongs, S. Chapter 15. HIV Protease Inhibitors. Annu. Rep. Med. Chem. 1994, 29, 133-144 and references cited therein.
3. Reich, S. H.; Melnick, M.; Davies, J. F. II; Appelt, K.; Lewis, K. K.; Fuhry, M.; Pino, M.; Trippe, A. J.; Nguyen, D.; Dawson, H.; Wu, B.; Musick, L.; Kosa, M.; Kahil, D.; Webber, S.; Gehlhaar, D. K.; Andrada, D.; Shetty, B. Protein Structure-based Design of Potent Orally Bioavailable Nonpeptide Inhibitors of Human Immuniodeficiency Virus Protease. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 3298-3302.
4. Roberts, N. A.; Martin, J. A.; Kinchington, D.; Broadhurst, A. V.; Craig, J. C.; et al. Rational Design of Peptide-Based HIV Proteinase Inhibitors. Science 1990, 248, 358-361.
5. Kaldor, S. W.; Hammond, M.; Dressman, B. A.; Fritz, J. E.; Crowell, T. A.; Hermann, R. A. New Dipeptide Isosteres Useful for the Inhibition of HIV-1 Protease. Bioorg. Med. Chem. Lett. 1994, 11, 1385-1390.
6. See ref 3 for crystallization conditions, data collection, and structure solution of HIV-Pr complexes.
7. In retrospect, the lack of activity of compounds such as 3 is likely a result of their strong conformational preferences. Compound 3 contains an acylated aniline with only one ortho substituent (the thioalkyl chain), so that a conformation where the amide linkage is in the plane of the phenyl ring is of lower energy. In this conformation the amide carbonyl cannot reach the flap water molecule to form a hydrogen bond. This is not the case with benzamides such as 4, where the in-plane conformation is of higher energy.
8. Lipton, M. F.; Basha, A.; Weinreb, S. M. Conversion of Esters to Amides with Dimethylaluminum Amides: N,N-Dimethylcy-clohexanecarboxamide. Org. Synth. 1979, 59, 492-495.
9. Havens, S. J.; Hergenrother, M. Synthesis of Arylacetylenes by the Sodium Hydride Catalyzed Cleavage of 4-Aryl-2-methyl-3-butyn-2-ols. J. Org. Chem. 1985, 50, 10, 1763-1765.
10. R-Dimethyl-11-tetradecen-1-ol Acetate via a Thiophenol-mediated Olefin Inversion. J. Org. Chem. 1986, 51, 260-263.
11. Chini, M.; Crotti, P.; Macchia, F. Metal Salts as New Catalysts for Mild and Efficient Aminolysis of Oxiranes. Tetrahedron Lett. 1990, 31, 32, 4661-4664.
12. Melnick, M.; Reich, S. H.; Lewis, K. K.; Mitchell, L. J.; Nguyen, D.; Trippe, A. J.; Dawson, H.; Davies, J. F., II; Appelt, K.; Wu, B.-W.; Musick, L.; Gehlhaar, D. K.; Webber, S.; Shetty, B.; Kosa, M.; Kahil, D.; Andrada, D. Bis Tertiary Amide Inhibitors of the HIV-1 Protease Generated via Protein Structure-Based Iterative Design. J. Med. Chem. 1996, 39, 2795-2811.
13. Dale, W. J.; Starr, L.; Strobel, C. W. Substituted Styrenes. VI. Syntheses of the Isomeric Formylstyrenes and o- and m-Vinylbenzoic Acid. J. Org. Chem. 1961, 26, 2225-2227.