title: Discovery of GS-9669, a thumb site II non-nucleoside inhibitor of NS5B for the treatment of genotype 1 chronic hepatitis C infection.
abstract: Investigation of thiophene-2-carboxylic acid HCV NS5B site II inhibitors, guided by measurement of cell culture medium binding, revealed the structure-activity relationships for intrinsic cellular potency. The pharmacokinetic profile was enhanced through incorporation of heterocyclic ethers on the N-alkyl substituent. Hydroxyl groups were incorporated to modulate protein binding. Intrinsic potency was further improved through enantiospecific introduction of an olefin in the N-acyl motif, resulting in the discovery of the phase 2 clinical candidate GS-9669. The unexpected activity of this compound against the clinically relevant NS5B M423T mutant, relative to the wild type, was shown to arise from both the N-alkyl substituent and the N-acyl group.
authors.affiliation: Gilead Sciences, Inc. , 333 Lakeside Drive, Foster City, California 94404, United States.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Lazerwith
authors.forename: Willard
authors.initials: W
authors.lastname: Lew
authors.forename: Jennifer
authors.initials: J
authors.lastname: Zhang
authors.forename: Philip
authors.initials: P
authors.lastname: Morganelli
authors.forename: Qi
authors.initials: Q
authors.lastname: Liu
authors.forename: Eda
authors.initials: E
authors.lastname: Canales
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.forename: Daniel
authors.initials: D
authors.lastname: Byun
authors.forename: Michael
authors.initials: M
authors.lastname: Mertzman
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Lee
authors.initials: L
authors.lastname: Chong
authors.forename: Lianhong
authors.initials: L
authors.lastname: Xu
authors.forename: Todd
authors.initials: T
authors.lastname: Appleby
authors.forename: Xiaowu
authors.initials: X
authors.lastname: Chen
authors.forename: Martijn
authors.initials: M
authors.lastname: Fenaux
authors.forename: Ahmad
authors.initials: A
authors.lastname: Hashash
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Leavitt
authors.forename: Eric
authors.initials: E
authors.lastname: Mabery
authors.forename: Mike
authors.initials: M
authors.lastname: Matles
authors.forename: Judy W
authors.initials: JW
authors.lastname: Mwangi
authors.forename: Yang
authors.initials: Y
authors.lastname: Tian
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Lee
authors.forename: Jingyu
authors.initials: J
authors.lastname: Zhang
authors.forename: Christine
authors.initials: C
authors.lastname: Zhu
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Murray
authors.forename: William J
authors.initials: WJ
authors.lastname: Watkins
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013876:Thiophenes / Q000737:chemistry / Q000494:pharmacology*; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D005663:Furans; D013876:Thiophenes; D017361:Viral Nonstructural Proteins; C582393:GS-9669; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase