Journal of medicinal chemistry · 2009
Phosphoramidate prodrugs of 2'-C-methylcytidine for therapy of hepatitis C virus infection.
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Gardelli Cristina, Attenni Barbara, Donghi Monica, Meppen Malte, Pacini Barbara, Harper Steven, Di Marco Annalise, Fiore Fabrizio, Giuliano Claudio, Pucci Vincenzo, Laufer Ralph, Gennari Nadia, Marcucci Isabella, Leone Joseph F, Olsen David B, MacCoss Malcolm, Rowley Michael, Narjes Frank
Аннотация
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.