title: 4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters.
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.
authors: Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Susan.hagen@pfizer.com
authors: S E
authors: SE
authors: Hagen
authors: J
authors: J
authors: Domagala
authors: C
authors: C
authors: Gajda
authors: M
authors: M
authors: Lovdahl
authors: B D
authors: BD
authors: Tait
authors: E
authors: E
authors: Wise
authors: T
authors: T
authors: Holler
authors: D
authors: D
authors: Hupe
authors: C
authors: C
authors: Nouhan
authors: A
authors: A
authors: Urumov
authors: G
authors: G
authors: Zeikus
authors: E
authors: E
authors: Zeikus
authors: E A
authors: EA
authors: Lunney
authors: A
authors: A
authors: Pavlovsky
authors: S J
authors: SJ
authors: Gracheck
authors: J
authors: J
authors: Saunders
authors: S
authors: S
authors: VanderRoest
authors: J
authors: J
authors: Brodfuehrer
mesh_terms: D000818:Animals; D001682:Biological Availability; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D006678:HIV / Q000187:drug effects; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015497:HIV-1 / Q000201:enzymology; D006801:Humans; D008214:Lymphocytes / Q000821:virology; D051379:Mice; D009154:Mutation; D011753:Pyrones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C430900:3-(2-tert-butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-6-isopropyl-6-(2-thiophen-3-ylethyl)-5,6-dihydropyran-2-one; D017320:HIV Protease Inhibitors; D011753:Pyrones; D013440:Sulfides; D016333:HIV Protease