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

Bioorg Med Chem Lett. 2009 Mar 1;19(5):1392-5. doi: 10.1016/j.bmcl.2009.01.035. Epub 2009 Jan 19.

Abstract

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.

Publication types

  • Comparative Study

MeSH terms

  • Amides / chemical synthesis*
  • Amides / pharmacology
  • Animals
  • Cells, Cultured
  • Cytidine / analogs & derivatives*
  • Cytidine / chemical synthesis*
  • Cytidine / pharmacology
  • Dogs
  • Drug Evaluation, Preclinical / methods
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology
  • Hepatocytes / drug effects
  • Hepatocytes / enzymology
  • Hepatocytes / virology
  • Humans
  • Phosphoric Acids / chemical synthesis*
  • Phosphoric Acids / pharmacology
  • Prodrugs / chemical synthesis*
  • Prodrugs / pharmacology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / metabolism
  • Rabbits
  • Rats
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Amides
  • Phosphoric Acids
  • Prodrugs
  • Viral Nonstructural Proteins
  • 2'-C-methylcytidine
  • Cytidine
  • phosphoramidic acid
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase