title: Design, synthesis, and antiviral properties of 4'-substituted ribonucleosides as inhibitors of hepatitis C virus replication: the discovery of R1479.
abstract: A series of 4'-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4'-azidocytidine, R1479) with an IC(50) of 1.28 microM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC(50)=320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.
authors.affiliation: Medicinal Chemistry, Roche Palo Alto LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. Dave.Smith@Roche.com
authors.forename: David B
authors.initials: DB
authors.lastname: Smith
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Martin
authors.forename: Klaus
authors.initials: K
authors.lastname: Klumpp
authors.forename: Stewart J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Peter A
authors.initials: PA
authors.lastname: Blomgren
authors.forename: Rene
authors.initials: R
authors.lastname: Devos
authors.forename: Caroline
authors.initials: C
authors.lastname: Granycome
authors.forename: Julie
authors.initials: J
authors.lastname: Hang
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Hobbs
authors.forename: Wen-Rong
authors.initials: WR
authors.lastname: Jiang
authors.forename: Carl
authors.initials: C
authors.lastname: Laxton
authors.forename: Sophie
authors.initials: S
authors.lastname: Le Pogam
authors.forename: Vincent
authors.initials: V
authors.lastname: Leveque
authors.forename: Han
authors.initials: H
authors.lastname: Ma
authors.forename: Graham
authors.initials: G
authors.lastname: Maile
authors.forename: John H
authors.initials: JH
authors.lastname: Merrett
authors.forename: Arkadius
authors.initials: A
authors.lastname: Pichota
authors.forename: Keshab
authors.initials: K
authors.lastname: Sarma
authors.forename: Mark
authors.initials: M
authors.lastname: Smith
authors.forename: Steven
authors.initials: S
authors.lastname: Swallow
authors.forename: Julian
authors.initials: J
authors.lastname: Symons
authors.forename: David
authors.initials: D
authors.lastname: Vesey
authors.forename: Isabel
authors.initials: I
authors.lastname: Najera
authors.forename: Nick
authors.initials: N
authors.lastname: Cammack
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003562:Cytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016174:Hepacivirus / Q000235:genetics*; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry; D012313:RNA / Q000737:chemistry; D012263:Ribonucleosides / Q000737:chemistry*; D014529:Uridine; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides; D012263:Ribonucleosides; D003562:Cytidine; D012313:RNA; C508950:4'-azidocytidine; D014529:Uridine