Structure-Based Design of Nonpeptidic HIV Protease Inhibitors:  The Sulfonamide-Substituted Cyclooctylpyranones

• Published in: Journal of medicinal chemistry Vol. 40; no. 7; pp. 1149 - 1164
• Main Authors: Skulnick, Harvey I, Johnson, Paul D, Aristoff, Paul A, Morris, Jeanette K, Lovasz, Kristine D, Howe, W. Jeffrey, Watenpaugh, Keith D, Janakiraman, Musiri N, Anderson, David J, Reischer, Robert J, Schwartz, Theresa M, Banitt, Lee S, Tomich, Paul K, Lynn, Janet C, Horng, Miao-Miao, Chong, Kong-Teck, Hinshaw, Roger R, Dolak, Lester A, Seest, Eric P, Schwende, Francis J, Rush, Bob D, Howard, Gina M, Toth, Lisa N, Wilkinson, Karen R, Kakuk, Thomas J, Johnson, Carol W, Cole, Serena L, Zaya, Renee M, Zipp, Gail L, Possert, Peggy L, Dalga, Robert J, Zhong, Wei-Zhu, Williams, Marta G, Romines, Karen R
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.03.1997; Amer Chemical Soc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Chemistry, Medicinal; human immunodeficiency virus; Life Sciences & Biomedicine; Medical sciences; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; 4-HYDROXY-2-PYRONES; AIDS; 4-HYDROXYCOUMARINS; Cyclopropane derivatives; Intravenous administration; Rat; Non peptide compound; Binding site; Oxygen heterocycle; Modeling; Structure activity relation; Molecular model; Bicyclic compound; Lentivirinae; Antiviral; Monte Carlo method; Sulfonamide; Enzyme; Rodentia; Benzene derivatives; Retroviridae; Enzyme inhibitor; Lactone; Inhibitor enzyme complex; In vitro; Virus; In vivo; Peptidases; Vertebrata; Mammalia; Animal; Hydrolases; Human immunodeficiency virus; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm960441m

Recently, cyclooctylpyranone derivatives with m-carboxamide substituents (e.g. 2c) were identified as potent, nonpeptidic HIV protease inhibitors, but these compounds lacked significant antiviral activity in cell culture. Substitution of a sulfonamide group at the meta position, however, produces compounds with excellent HIV protease binding affinity and antiviral activity. Guided by an iterative structure-based drug design process, we have prepared and evaluated a number of these derivatives, which are readily available via a seven-step synthesis. A few of the most potent compounds were further evaluated for such characteristics as pharmacokinetics and toxicity in rats and dogs. From this work, the p-cyanophenyl sulfonamide derivative 35k emerged as a promising inhibitor, was selected for further development, and entered phase I clinical trials.