Synthesis and evaluation of novel phosphoramidate prodrugs of 2′-methyl cytidine as inhibitors of hepatitis c virus NS5B polymerase

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 5; pp. 1392 - 1395
• Main Authors: Donghi, Monica, Attenni, Barbara, Gardelli, Cristina, Marco, Annalise Di, Fiore, Fabrizio, Giuliano, Claudio, Laufer, Ralph, Leone, Joseph F., Pucci, Vincenzo, Rowley, Michael, Narjes, Frank
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01-03-2009
• Subjects: Amides - chemical synthesis; Amides - pharmacology; Animals; Antiviral; Cells, Cultured; Cytidine - analogs & derivatives; Cytidine - chemical synthesis; Cytidine - pharmacology; Dogs; Drug Evaluation, Preclinical - methods; HCV polymerase; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepatitis C virus; Hepatocytes - drug effects; Hepatocytes - enzymology; Hepatocytes - virology; Humans; Phosphoramidates; Phosphoric Acids - chemical synthesis; Phosphoric Acids - pharmacology; Prodrugs; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Rabbits; Rats; RNA-Dependent RNA Polymerase - antagonists & inhibitors; RNA-Dependent RNA Polymerase - metabolism; Triphosphate; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; HCV polymerase; Antiviral; Phosphoramidates; Prodrugs; Triphosphate
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.01.035

The synthesis and SAR of phosphoramidate prodrugs of 2′-methyl cytidine as inhibitors of HCV NS5B polymerase is reported.
A variety of new prodrugs of 2′-methyl cytidine based on acyloxy ethylamino phosphoramidates have been synthesized and tested in vitro and in vivo for their biological activity. Compared with the parent drug a 10- to 20-fold increase in formation of nucleotide triphosphate in rat and human hepatocytes could be achieved.