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

  • J Med Chem. 2001 Jul 5;44(14):2319-32. doi: 10.1021/jm0003844.
S E Hagen  1 ,  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
Affiliations
  • 1. Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. [email protected]
PMID: 11428926 DOI: 10.1021/jm0003844
Abstract

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-tert-butyl-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.

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