Phosphoramidate Prodrugs of 2′-C-Methylcytidine for Therapy of Hepatitis C Virus Infection

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• 作者：Cristina Gardelli ; Barbara Attenni ; Monica Donghi ; Malte Meppen ; Barbara Pacini ; Steven Harper ; Annalise Di Marco ; Fabrizio Fiore ; Claudio Giuliano ; Vincenzo Pucci ; Ralph Laufer ; Nadia Gennari ; Isabel
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：September 10, 2009
• 年：2009
• 卷：52
• 期：17
• 页码：5394-5407
• 全文大小：1077K
• 年卷期：v.52,no.17(September 10, 2009)
• ISSN：1520-4804

文摘

The application of a phosphoramidate prodrug approach to 2′-C-methylcytidine (NM107), the first nucleoside inhibitor of the hepatitis C virus (HCV) NS5B polymerase, is reported. 2′-C-Methylcytidine, as its valyl ester prodrug (NM283), was efficacious in reducing the viral load in patients infected with HCV. Several of the phosphoramidates prepared demonstrated a 10- to 200-fold superior potency with respect to the parent nucleoside in the cell-based replicon assay. This is due to higher levels of 2′-C-methylcytidine triphosphate in the cells. These prodrugs are efficiently activated and converted to the triphosphate in hepatocytes of several species. Our SAR studies ultimately led to compounds that gave high levels of NTP in hamster and rat liver after subcutaneous dosing and that were devoid of the toxic phenol moiety usually found in ProTides.