| Autor: |
Hagen, S. E., Domagala, J., Gajda, C., Lovdahl, M., Tait, B. D., Wise, E., Holler, T., Hupe, D., Nouhan, C., Urumov, A., Zeikus, G., Zeikus, E., Lunney, E. A., Pavlovsky, A., Gracheck, S. J., Saunders, J., VanderRoest, S., Brodfuehrer, J. |
| Zdroj: |
Journal of Medicinal Chemistry; July 2001, Vol. 44 Issue: 14 p2319-2332, 14p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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