Design, synthesis, and antiviral properties of 4′-substituted ribonucleosides as inhibitors of hepatitis C virus replication: The discovery of R1479

A series of 4′-substituted ribonucleoside derivatives has been prepared and evaluated for inhibition of hepatitis C virus (HCV) RNA replication in cell culture. The most potent and non-cytotoxic derivative was compound 28 (4′-azidocytidine, R1479) with an IC50 of 1.28 μM in the HCV replicon system. The triphosphate of compound 28 was prepared and shown to be an inhibitor of RNA synthesis mediated by NS5B (IC50 = 320 nM), the RNA polymerase encoded by HCV. Data on related analogues have been used to generate some preliminary requirements for activity within this series of nucleosides.

Graphical abstractThe synthesis of 4′-substituted nucleosides as potential antiviral agents is reported.Figure optionsDownload full-size imageDownload as PowerPoint slide