Cyclic phosphoramidates as prodrugs of 2′-C-methylcytidine

The currently approved treatment for hepatitis C virus infections is a combination of Ribavirin and pegylated Interferon. It leads to a sustained virologic response in approximately only half of the patients treated. For this reason there is an urgent need of new therapeutic agents. 2′-C-Methylcytidine is the first nucleoside inhibitor of the HCV NS5B polymerase that was efficacious in reducing the viral load in patients infected with HCV. The application of a monophosphate prodrug approach based on unprecedented cyclic phosphoramidates is reported. Our SAR studies led to compounds that are efficiently converted to the active triphosphate in human hepatocytes.

A novel application of a cyclic phosphoramidate monophosphate prodrug approach to 2′-C-methylcytidine 4 led to compounds 3 that form appreciable levels of the active species triphosphate 6 in vivo.Figure optionsDownload as PowerPoint slide