TY - JOUR
T1 - 4-Hydroxy-5,6-dihydropyrones as inhibitors of HIV protease
T2 - The effect of heterocyclic substituents at C-6 on antiviral potency and pharmacokinetic parameters
AU - Hagen, S. E.
AU - Domagala, J.
AU - Gajda, C.
AU - Lovdahl, M.
AU - Tait, B. D.
AU - Wise, E.
AU - Holler, T.
AU - Hupe, D.
AU - Nouhan, C.
AU - Urumov, A.
AU - Zeikus, G.
AU - Zeikus, E.
AU - Lunney, E. A.
AU - Pavlovsky, A.
AU - Gracheck, S. J.
AU - Saunders, J.
AU - VanderRoest, S.
AU - Brodfuehrer, J.
PY - 2001/7/5
Y1 - 2001/7/5
N2 - 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.
AB - 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.
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U2 - 10.1021/jm0003844
DO - 10.1021/jm0003844
M3 - Article
C2 - 11428926
AN - SCOPUS:0035811452
SN - 0022-2623
VL - 44
SP - 2319
EP - 2332
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 14
ER -