title: 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.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, La Jolla Laboratories, San Diego, California 92121, USA. hui.li@pfizer.com
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Tatlock
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Javier
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Tanya
authors.initials: T
authors.lastname: Jewell
authors.forename: Leena
authors.initials: L
authors.lastname: Patel
authors.forename: Sarah
authors.initials: S
authors.lastname: Ludlum
authors.forename: Matthew
authors.initials: M
authors.lastname: Drowns
authors.forename: Sadayappan V
authors.initials: SV
authors.lastname: Rahavendran
authors.forename: Heather
authors.initials: H
authors.lastname: Skor
authors.forename: Robert
authors.initials: R
authors.lastname: Hunter
authors.forename: Stephanie T
authors.initials: ST
authors.lastname: Shi
authors.forename: Koleen J
authors.initials: KJ
authors.lastname: Herlihy
authors.forename: Hans
authors.initials: H
authors.lastname: Parge
authors.forename: Michael
authors.initials: M
authors.lastname: Hickey
authors.forename: Xiu
authors.initials: X
authors.lastname: Yu
authors.forename: Fannie
authors.initials: F
authors.lastname: Chau
authors.forename: Jim
authors.initials: J
authors.lastname: Nonomiya
authors.forename: Cristina
authors.initials: C
authors.lastname: Lewis
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D018360:Crystallography, X-Ray; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004285:Dogs; D016174:Hepacivirus / Q000201:enzymology*; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D011753:Pyrones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011743:Pyrimidines
chemical_list: D000998:Antiviral Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011753:Pyrones; D012324:RNA-Dependent RNA Polymerase; D014230:Triazoles; C550357:filibuvir; D011743:Pyrimidines