title: 6-Hydrazinopurine 2'-methyl ribonucleosides and their 5'-monophosphate prodrugs as potent hepatitis C virus inhibitors.
abstract: A series of 6-hydrazinopurine 2'-methyl ribonucleosides was synthesized and tested for its inhibitory activity against the hepatitis C virus (HCV). The lack of antiviral activity of these nucleosides was associated with a poor affinity for adenosine kinase, which prompted us to synthesize several of their 5'-monophosphate prodrugs. Some of these prodrugs exhibited more than 1000-fold improvement in anti-HCV activity when compared to their parent nucleosides (EC(50) of 24 nM vs 92 microM for the parent).
authors.affiliation: Valeant Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
authors.forename: Esmir
authors.initials: E
authors.lastname: Gunic
authors.forename: Suetying
authors.initials: S
authors.lastname: Chow
authors.forename: Frank
authors.initials: F
authors.lastname: Rong
authors.forename: Kanda
authors.initials: K
authors.lastname: Ramasamy
authors.forename: Anneke
authors.initials: A
authors.lastname: Raney
authors.forename: David Yunzhi
authors.initials: DY
authors.lastname: Li
authors.forename: Jingfan
authors.initials: J
authors.lastname: Huang
authors.forename: Robert K
authors.initials: RK
authors.lastname: Hamatake
authors.forename: Zhi
authors.initials: Z
authors.lastname: Hong
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Girardet
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; D010710:Phosphates / Q000737:chemistry*; D011355:Prodrugs; D012263:Ribonucleosides / Q000737:chemistry*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D010710:Phosphates; D011355:Prodrugs; D012263:Ribonucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase