Cyclic monophosphate prodrugs of base-modified 2'-C-methyl ribonucleosides as potent inhibitors of hepatitis C virus RNA replication.
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).
Gunic
Esmir
E
Valeant Research & Development, 3300 Hyland Avenue, Costa Mesa, CA 92626, USA. egunic@ardeabio.com
Girardet
Jean-Luc
JL
Ramasamy
Kanda
K
Stoisavljevic-Petkov
Vesna
V
Chow
Suetying
S
Yeh
Li-Tain
LT
Hamatake
Robert K
RK
Raney
Anneke
A
Hong
Zhi
Z
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*
D000998:Antiviral Agents; D009712:Nucleotides, Cyclic; D011355:Prodrugs; D012263:Ribonucleosides