title: Discovery of a 2'-fluoro-2'-C-methyl C-nucleotide HCV polymerase inhibitor and a phosphoramidate prodrug with favorable properties.
abstract: A series of 2'-fluorinated C-nucleosides were prepared and tested for anti-HCV activity. Among them, the triphosphate of 2'-fluoro-2'-C-methyl adenosine C-nucleoside (15) was a potent and selective inhibitor of the NS5B polymerase and maintained activity against the S282T resistance mutant. A number of phosphoramidate prodrugs were then prepared and evaluated leading to the identification of the 1-aminocyclobutane-1-carboxylic acid isopropyl ester variant (53) with favorable pharmacokinetic properties including efficient liver delivery in animals.
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA. Electronic address: tkirschberg@gilead.com.
authors.forename: Thorsten A
authors.initials: TA
authors.lastname: Kirschberg
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Sammy
authors.initials: S
authors.lastname: Metobo
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Michael O
authors.initials: MO
authors.lastname: Clarke
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Vangelis
authors.initials: V
authors.lastname: Aktoudianakis
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Darius
authors.initials: D
authors.lastname: Babusis
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Ona
authors.initials: O
authors.lastname: Barauskas
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Birkus
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Butler
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Byun
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Chin
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Doerffler
authors.affiliation: Beryllium, 7869 NE Day Road West, Bainbridge Island, WA 98110, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Edwards
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Martijn
authors.initials: M
authors.lastname: Fenaux
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Rick
authors.initials: R
authors.lastname: Lee
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Willard
authors.initials: W
authors.lastname: Lew
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Mish
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Murakami
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Yeojin
authors.initials: Y
authors.lastname: Park
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Neil H
authors.initials: NH
authors.lastname: Squires
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Tirunagari
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Whitcomb
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Xu
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Huiling
authors.initials: H
authors.lastname: Yang
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Lijun
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Appleby
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Joy Y
authors.initials: JY
authors.lastname: Feng
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Adrian S
authors.initials: AS
authors.lastname: Ray
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Aesop
authors.initials: A
authors.lastname: Cho
authors.affiliation: Gilead Sciences, 333 Lakeside Drive, Foster City, CA 94404, USA.
authors.forename: Choung U
authors.initials: CU
authors.lastname: Kim
mesh_terms: D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D018938:Caco-2 Cells; D002460:Cell Line; D006224:Cricetinae; D055808:Drug Discovery; D024882:Drug Resistance, Viral; D054879:Halogenation; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008745:Methylation; D062105:Molecular Docking Simulation; D009705:Nucleosides / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D010756:Phosphoric Acids / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017354:Point Mutation; D011355:Prodrugs / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000577:Amides; D000998:Antiviral Agents; D009705:Nucleosides; D010756:Phosphoric Acids; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C011067:phosphoramidic acid; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Antiviral; C-nucleoside; Hepatitis C; NS5B polymerase