4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease: the effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters.
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.
Hagen
S E
SE
Department of Chemistry, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Susan.hagen@pfizer.com
Domagala
J
J
Gajda
C
C
Lovdahl
M
M
Tait
B D
BD
Wise
E
E
Holler
T
T
Hupe
D
D
Nouhan
C
C
Urumov
A
A
Zeikus
G
G
Zeikus
E
E
Lunney
E A
EA
Pavlovsky
A
A
Gracheck
S J
SJ
Saunders
J
J
VanderRoest
S
S
Brodfuehrer
J
J
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
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