6-Hydrazinopurine 2'-methyl ribonucleosides and their 5'-monophosphate prodrugs as potent hepatitis C virus inhibitors.
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).
Gunic
Esmir
E
Valeant Research and Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA.
Chow
Suetying
S
Rong
Frank
F
Ramasamy
Kanda
K
Raney
Anneke
A
Li
David Yunzhi
DY
Huang
Jingfan
J
Hamatake
Robert K
RK
Hong
Zhi
Z
Girardet
Jean-Luc
JL
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
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