title: Discovery of the first C-nucleoside HCV polymerase inhibitor (GS-6620) with demonstrated antiviral response in HCV infected patients.
abstract: Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, and they are likely to become a key component of future treatment regimens. NI candidates that have entered clinical development thus far have all been N-nucleoside derivatives. Herein, we report the discovery of a C-nucleoside class of NS5B inhibitors. Exploration of adenosine analogs in this class identified 1'-cyano-2'-C-methyl 4-aza-7,9-dideaza adenosine as a potent and selective inhibitor of NS5B. A monophosphate prodrug approach afforded a series of compounds showing submicromolar activity in HCV replicon assays. Further pharmacokinetic optimization for sufficient oral absorption and liver triphosphate loading led to identification of a clinical development candidate GS-6620. In a phase I clinical study, the potential for potent activity was demonstrated but with high intra- and interpatient pharmacokinetic and pharmacodynamic variability.
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, California 94044, United States.
authors.forename: Aesop
authors.initials: A
authors.lastname: Cho
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.forename: Rick
authors.initials: R
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Butler
authors.forename: Sammy
authors.initials: S
authors.lastname: Metobo
authors.forename: Vangelis
authors.initials: V
authors.lastname: Aktoudianakis
authors.forename: Willard
authors.initials: W
authors.lastname: Lew
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Michael
authors.initials: M
authors.lastname: Clarke
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.forename: Daniel
authors.initials: D
authors.lastname: Byun
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.forename: Darius
authors.initials: D
authors.lastname: Babusis
authors.forename: Anne C
authors.initials: AC
authors.lastname: Carey
authors.forename: Polina
authors.initials: P
authors.lastname: German
authors.forename: Dorothea
authors.initials: D
authors.lastname: Sauer
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhong
authors.forename: Stephen
authors.initials: S
authors.lastname: Rossi
authors.forename: Martijn
authors.initials: M
authors.lastname: Fenaux
authors.forename: John G
authors.initials: JG
authors.lastname: McHutchison
authors.forename: Jason
authors.initials: J
authors.lastname: Perry
authors.forename: Joy
authors.initials: J
authors.lastname: Feng
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D016174:Hepacivirus / Q000201:enzymology*; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology / Q000821:virology; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D009943:Organophosphorus Compounds; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase