Cyclic phosphoramidates as prodrugs of 2'-C-methylcytidine

Eur J Med Chem. 2009 Sep;44(9):3765-70. doi: 10.1016/j.ejmech.2009.04.043.

Malte Meppen ¹, Barbara Pacini, Renzo Bazzo, Uwe Koch, Joseph F Leone, Kenneth A Koeplinger, Michael Rowley, Sergio Altamura, Annalise Di Marco, Fabrizio Fiore, Claudio Giuliano, Odalys Gonzalez-Paz, Ralph Laufer, Vincenzo Pucci, Frank Narjes, Cristina Gardelli

Affiliations

Affiliation

1 Department of Chemistry-Istituto di Ricerche di Biologia Molecolare, P. Angeletti S.p.A. (IRBM-MRL Rome), Via Pontina Km 30.600, 00040 Pomezia, Italy.

PMID: 19493593 DOI: 10.1016/j.ejmech.2009.04.043

Abstract

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.

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