title: Cyclic monophosphate prodrugs of base-modified 2'-C-methyl ribonucleosides as potent inhibitors of hepatitis C virus RNA replication.
abstract: A new series of heterobase-modified 2'-C-methyl ribonucleosides was synthesized and tested as inhibitors of hepatitis C virus (HCV) RNA replication. The nucleosides showed a weak inhibitory activity in a HCV replicon system (EC(50)=92 microM) and did not exhibit any cytotoxicity (CC(50)>300 microM). Cyclic monophosphate (cMP) prodrugs of the same nucleosides were synthesized and also tested in the HCV replicon system. Prodrugs exhibited strong potency (EC(50)=0.008 microM) without significant cytotoxicity (CC(50)>50 microM).
authors.affiliation: Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. egunic@ardeabio.com
authors.forename: Esmir
authors.initials: E
authors.lastname: Gunic
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Girardet
authors.forename: Kanda
authors.initials: K
authors.lastname: Ramasamy
authors.forename: Vesna
authors.initials: V
authors.lastname: Stoisavljevic-Petkov
authors.forename: Suetying
authors.initials: S
authors.lastname: Chow
authors.forename: Li-Tain
authors.initials: LT
authors.lastname: Yeh
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hamatake
authors.forename: Anneke
authors.initials: A
authors.lastname: Raney
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D016174:Hepacivirus / Q000235:genetics*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D008956:Models, Chemical; D008968:Molecular Conformation; D009712:Nucleotides, Cyclic / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis*; D012263:Ribonucleosides / Q000737:chemistry*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D009712:Nucleotides, Cyclic; D011355:Prodrugs; D012263:Ribonucleosides