The phosphoramidate ProTide approach greatly enhances the activity of β-2′-C-methylguanosine against hepatitis C virus

beta-2'-C-Methyl purines (1, 2) are known inhibitors of hepatitis C virus (HCV). We herein report the synthesis, biological and enzymatic evaluation of their 5'-phosphoramidate ProTides. Described herein are seven L-alanine phosphoramidate derivatives with variations to the amino acid ester. The 1-naphthyl phosphoramidate of beta-2'-methylguanosine containing the benzyl ester (20) was the most active at 0.12 mu M, an 84-fold of increase in activity compared to the parent nucleoside (2) with no increase of cytotoxicity. The carboxypeptidase mediated hydrolysis of several ProTides showed a predictive correlation with their activity versus HCV in replicon. (C) 2009 Elsevier Ltd. All rights reserved.