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

Autor:	Javier Gonzalez, Jim Nonomiya, Angelica Linton, Leena Patel, Hui Li, Fannie Chau, Hans E. Parge, Sadayappan V. Rahavendran, Heather Skor, Michael J. Hickey, Tanya Michelle Jewell, Matthew Drowns, Stephanie T. Shi, Robert P. Hunter, Cristina Lewis, Sarah Ludlum, Tatlock John H, Koleen J. Herlihy, Xiu Yu
Rok vydání:	2009
Předmět:	Models Molecular Dihydropyran Stereochemistry Hepatitis C virus Administration Oral Hepacivirus Crystallography X-Ray medicine.disease_cause Antiviral Agents Rats Sprague-Dawley Structure-Activity Relationship chemistry.chemical_compound Dogs Cytochrome P-450 CYP2D6 Inhibitors RNA polymerase Drug Discovery medicine Animals Transferase chemistry.chemical_classification Bicyclic molecule biology virus diseases Stereoisomerism Triazoles RNA-Dependent RNA Polymerase digestive system diseases Rats Macaca fascicularis Enzyme Solubility chemistry Pyrones Enzyme inhibitor Microsomes Liver biology.protein Molecular Medicine Lactone
Zdroj:	Journal of Medicinal Chemistry. 52:1255-1258
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::516b6514f4d3e027e767a1cee7f347f3 https://doi.org/10.1021/jm8014537 Zobrazit plný text záznamu