title: Discovery of tricyclic 5,6-dihydro-1H-pyridin-2-ones as novel, potent, and orally bioavailable inhibitors of HCV NS5B polymerase.
abstract: A novel series of non-nucleoside small molecules containing a tricyclic dihydropyridinone structural motif was identified as potent HCV NS5B polymerase inhibitors. Driven by structure-based design and building on our previous efforts in related series of molecules, we undertook extensive SAR studies, in which we identified a number of metabolically stable and very potent compounds in genotype 1a and 1b replicon assays. This work culminated in the discovery of several inhibitors, which combined potent in vitro antiviral activity against both 1a and 1b genotypes, metabolic stability, good oral bioavailability, and high C(12) (PO)/EC(50) ratios.
authors.affiliation: Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc., 5871 Oberlin Drive, Suite 200, San Diego, CA 92121, USA. fruebsam@anadyspharma.com
authors.forename: Frank
authors.initials: F
authors.lastname: Ruebsam
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Murphy
authors.forename: Chinh V
authors.initials: CV
authors.lastname: Tran
authors.forename: Lian-Sheng
authors.initials: LS
authors.lastname: Li
authors.forename: Jingjing
authors.initials: J
authors.lastname: Zhao
authors.forename: Peter S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: Helen M
authors.initials: HM
authors.lastname: McGuire
authors.forename: Alan X
authors.initials: AX
authors.lastname: Xiang
authors.forename: Zhongxiang
authors.initials: Z
authors.lastname: Sun
authors.forename: Benjamin K
authors.initials: BK
authors.lastname: Ayida
authors.forename: Julie K
authors.initials: JK
authors.lastname: Blazel
authors.forename: Sun Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: Yuefen
authors.initials: Y
authors.lastname: Zhou
authors.forename: Qing
authors.initials: Q
authors.lastname: Han
authors.forename: Charles R
authors.initials: CR
authors.lastname: Kissinger
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Richard E
authors.initials: RE
authors.lastname: Showalter
authors.forename: Amit M
authors.initials: AM
authors.lastname: Shah
authors.forename: Mei
authors.initials: M
authors.lastname: Tsan
authors.forename: Rupal A
authors.initials: RA
authors.lastname: Patel
authors.forename: Peggy A
authors.initials: PA
authors.lastname: Thompson
authors.forename: Laurie A
authors.initials: LA
authors.lastname: Lebrun
authors.forename: Huiying J
authors.initials: HJ
authors.lastname: Hou
authors.forename: Ruhi
authors.initials: R
authors.lastname: Kamran
authors.forename: Maria V
authors.initials: MV
authors.lastname: Sergeeva
authors.forename: Darian M
authors.initials: DM
authors.lastname: Bartkowski
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Nolan
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Norris
authors.forename: Julia
authors.initials: J
authors.lastname: Khandurina
authors.forename: Jennifer
authors.initials: J
authors.lastname: Brooks
authors.forename: Ellen
authors.initials: E
authors.lastname: Okamoto
authors.forename: Leo
authors.initials: L
authors.lastname: Kirkovsky
mesh_terms: D000998:Antiviral Agents / Q000493:pharmacokinetics; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D018360:Crystallography, X-Ray; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects; D006526:Hepatitis C; D015394:Molecular Structure; D012324:RNA-Dependent RNA Polymerase; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; D012324:RNA-Dependent RNA Polymerase