| Discovery of (R)-6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one (PF-00868554) as a potent and orally available hepatitis C virus polymerase inhibitor. | |
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MedLine Citation:
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PMID: 19209845 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The HCV RNA-dependent RNA polymerase has emerged as one of the key targets for novel anti-HCV therapy development. Herein, we report the optimization of the dihydropyrone series inhibitors to improve compound aqueous solubility and reduce CYP2D6 inhibition, which led to the discovery of compound 24 (PF-00868554). Compound 24 is a potent and selective HCV polymerase inhibitor with a favorable pharmacokinetic profile and has recently entered a phase II clinical evaluation in patients with genotype 1 HCV. |
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Authors:
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Hui Li; John Tatlock; Angelica Linton; Javier Gonzalez; Tanya Jewell; Leena Patel; Sarah Ludlum; Matthew Drowns; Sadayappan V Rahavendran; Heather Skor; Robert Hunter; Stephanie T Shi; Koleen J Herlihy; Hans Parge; Michael Hickey; Xiu Yu; Fannie Chau; Jim Nonomiya; Cristina Lewis |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Journal of medicinal chemistry Volume: 52 ISSN: 1520-4804 ISO Abbreviation: J. Med. Chem. Publication Date: 2009 Mar |
Date Detail:
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Created Date: 2010-06-03 Completed Date: 2010-06-29 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9716531 Medline TA: J Med Chem Country: United States |
Other Details:
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Languages: eng Pagination: 1255-8 Citation Subset: IM |
Affiliation:
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Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. hui.li@pfizer.com |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Administration, Oral Animals Antiviral Agents / chemical synthesis*, pharmacokinetics, pharmacology Crystallography, X-Ray Cytochrome P-450 CYP2D6 / antagonists & inhibitors Dogs Hepacivirus / enzymology* Macaca fascicularis Microsomes, Liver / metabolism Models, Molecular Pyrones / chemical synthesis*, pharmacokinetics, pharmacology RNA Replicase / antagonists & inhibitors* Rats Rats, Sprague-Dawley Solubility Stereoisomerism Structure-Activity Relationship Triazoles / chemical synthesis*, pharmacokinetics, pharmacology |
| Chemical | |
Reg. No./Substance:
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0/6-cyclopentyl-6-(2-(2,6-diethylpyridin-4-yl)ethyl)-3-((5,7-dimethyl-(1,2,4)triazolo(1,5-a)pyrimidin-2-yl)methyl)-4-hydroxy-5,6-dihydropyran-2-one; 0/Antiviral Agents; 0/Pyrones; 0/Triazoles; EC 1.14.14.1/Cytochrome P-450 CYP2D6; EC 2.7.7.48/RNA Replicase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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