Synthesis and anti-HCV activity of 3',4'-oxetane nucleosides.
Hepatitis C virus afflicts approximately 180 million people worldwide and currently there are no direct acting antiviral agents available to treat this disease. Our first generation nucleoside HCV inhibitor, RG7128 has already established proof-of-concept in the clinic and is currently in phase IIb clinical trials. As part of our continuing efforts to discover novel anti-HCV agents, 3',4'-oxetane cytidine and adenosine nucleosides were prepared as inhibitors of HCV RNA replication. These nucleosides were shown not to be inhibitors of HCV as determined in a whole cell subgenomic replicon assay. However, 2'-mono/diflouro analogs, 4, 5, and 6 were readily phosphorylated to their monophosphate metabolites by deoxycytidine kinase and their triphosphate derivatives were shown to be inhibitors of HCV NS5B polymerase in vitro. Lack of anti-HCV activity in the replicon assay may be due to the inability of the monophosphates to be converted to their corresponding diphosphates.
Chang
Wonsuk
W
Pharmasset, Inc., East, Princeton, NJ 08540, USA.
Du
Jinfa
J
Rachakonda
Suguna
S
Ross
Bruce S
BS
Convers-Reignier
Serge
S
Yau
Wei T
WT
Pons
Jean-Francois
JF
Murakami
Eisuke
E
Bao
Haiying
H
Steuer
Holly Micolochick
HM
Furman
Phillip A
PA
Otto
Michael J
MJ
Sofia
Michael J
MJ
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004988:Ethers, Cyclic / Q000737:chemistry*; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D009705:Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D004988:Ethers, Cyclic; D009705:Nucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C005287:oxetane