4-Hydroxy-5,6-dihydropyrones as Inhibitors of HIV Protease: The Effect of Heterocyclic Substituents at C-6 on Antiviral Potency and Pharmacokinetic Parameters
| Autor: | Bradley D. Tait, Susan Elizabeth Hagen, Michael Lovdahl, Eric Andrew Zeikus, Carolyn Nouhan, Joanne Brodfuehrer, Donald Hupe, Christopher Andrew Gajda, John M. Domagala, Greg Zeikus, Elizabeth A. Lunney, Steve Vanderroest, Alexander Pavlovsky, Andrej Urumov, James Saunders, Stephen J. Gracheck, Eric Wise, Tod P. Holler |
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| Rok vydání: | 2001 |
| Předmět: |
medicine.medical_treatment
Drug Evaluation Preclinical Biological Availability Sulfides Pharmacology Virus Cell Line Mice Structure-Activity Relationship Dogs HIV Protease Drug Discovery medicine Animals Humans Potency HIV Protease Inhibitor Protease inhibitor (pharmacology) Lymphocytes Chromatography High Pressure Liquid chemistry.chemical_classification Protease biology Chemistry HIV virus diseases Drug Resistance Microbial Stereoisomerism HIV Protease Inhibitors biology.organism_classification Rats Enzyme Pyrones Enzyme inhibitor Mutation Lentivirus HIV-1 biology.protein Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 44:2319-2332 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm0003844 |
| Popis: | 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: | OpenAIRE |
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