Structure-based design of nonpeptidic HIV protease inhibitors: the sulfonamide-substituted cyclooctylpyramones

J Med Chem. 1997 Mar 28;40(7):1149-64. doi: 10.1021/jm960441m.

H I Skulnick ¹, P D Johnson, P A Aristoff, J K Morris, K D Lovasz, W J Howe, K D Watenpaugh, M N Janakiraman, D J Anderson, R J Reischer, T M Schwartz, L S Banitt, P K Tomich, J C Lynn, M M Horng, K T Chong, R R Hinshaw, L A Dolak, E P Seest, F J Schwende, B D Rush, G M Howard, L N Toth, K R Wilkinson, K R Romines

Affiliations

Affiliation

1 Discovery Chemistry Research, Pharmacia and Upjohn, Kalamazoo, Michigan 49001, USA.

PMID: 9089336 DOI: 10.1021/jm960441m

Abstract

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.

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