Preparation and biological evaluation of 1'-cyano-2'-C-methyl pyrimidine nucleosides as HCV NS5B polymerase inhibitors

Bioorg Med Chem Lett. 2014 Jul 15;24(14):3092-5. doi: 10.1016/j.bmcl.2014.05.015. Epub 2014 May 22.

Abstract

The first synthesis of 1'-cyano-2'-C-methyl pyrimidine nucleosides is described. Anti-HCV activity of these nucleosides and their nucleotide phosphoramidate prodrugs was assessed and compared to the 1'-unsubstituted counterparts and to the related 1'-cyano-2'-C-methyl C-nucleoside parent of GS-6620.

Keywords: HCV antivirals; NS5B polymerase inhibitor; Nucleotide phosphoramidate prodrugs; Pyrimidine nucleoside analogs.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / drug effects*
  • Hepacivirus / enzymology*
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Nucleosides / chemical synthesis
  • Nucleosides / chemistry
  • Nucleosides / pharmacology*
  • Pyrimidine Nucleosides / chemical synthesis
  • Pyrimidine Nucleosides / chemistry
  • Pyrimidine Nucleosides / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / metabolism
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Enzyme Inhibitors
  • Nucleosides
  • Pyrimidine Nucleosides
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase