title: Synthesis and anti-HCV activity of 3',4'-oxetane nucleosides.
abstract: Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3',4'-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2'-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.
authors.affiliation: Pharmasset, Inc., East, Princeton, NJ 08540, USA.
authors.forename: Wonsuk
authors.initials: W
authors.lastname: Chang
authors.forename: Jinfa
authors.initials: J
authors.lastname: Du
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Ross
authors.forename: Serge
authors.initials: S
authors.lastname: Convers-Reignier
authors.forename: Wei T
authors.initials: WT
authors.lastname: Yau
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Pons
authors.forename: Eisuke
authors.initials: E
authors.lastname: Murakami
authors.forename: Haiying
authors.initials: H
authors.lastname: Bao
authors.forename: Holly Micolochick
authors.initials: HM
authors.lastname: Steuer
authors.forename: Phillip A
authors.initials: PA
authors.lastname: Furman
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Sofia
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000737:chemistry*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D009705:Nucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C005287:oxetane