4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: The effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters

S. E. Hagen, J. Domagala, C. Gajda, M. Lovdahl, B. D. Tait, E. Wise, T. Holler, D. Hupe, C. Nouhan, A. Urumov, G. Zeikus, E. Zeikus, E. A. Lunney, A. Pavlovsky, S. J. Gracheck, J. Saunders, S. VanderRoest, J. Brodfuehrer

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Due largely to the emergence of multi-drug-resistant HIV strains, the development of new HIV protease inhibitors remains a high priority for the pharmaceutical industry. Toward this end, we previously identified a 4-hydroxy-5,6-dihydropyrone lead compound (CI-1029, 1) which possesses excellent activity against the protease enzyme, good antiviral efficacy in cellular assays, and promising bioavailability in several animal species. The search for a suitable back-up candidate centered on the replacement of the aniline moiety at C-6 with an appropriately substituted heterocyle. In general, this series of heterocyclic inhibitors displayed good activity (in both enzymatic and cellular tests) and low cellular toxicity; furthermore, several analogues exhibited improved pharmacokinetic parameters in animal models. The compound with the best combination of high potency, low toxicity, and favorable bioavailabilty was (S)-3-(2-tertbutyl-4-hydroxymethyl-5-methyl-phenylsulfanyl)-4-hydroxy-6- isopropyl-6-(2-thiophen-3-yl-ethyl)-5,6-dihydro-pyran-2-one (13-(S)). This thiophene derivative also exhibited excellent antiviral efficacy against mutant HIV protease and resistant HIV strains. For these reasons, compound 13-(S) was chosen for further preclinical evaluation.

Original languageEnglish (US)
Pages (from-to)2319-2332
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number14
Publication statusPublished - Jul 5 2001


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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