Parallel synthesis of pteridine derivatives as potent inhibitors for hepatitis C virus NS5B RNA-dependent RNA polymerase

Bioorg Med Chem Lett. 2005 Feb 1;15(3):675-8. doi: 10.1016/j.bmcl.2004.11.028.

Abstract

From compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a pteridine hit compound with an IC(50) of 15 microM. Our SAR studies were focused on the different groups at the 6- and 7-positions, substitutions at the 4-position, and replacement of N(1) or N(3) with carbon in the pteridine ring. We found that NH or OH at 4-position is critical for the inhibitory activity. Furthermore, a hydrophobic substituent at the 4-position may help compounds permeate through the cell membrane.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Hepacivirus / enzymology*
  • Humans
  • Inhibitory Concentration 50
  • Pteridines / chemical synthesis*
  • Pteridines / pharmacology*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • Replicon / drug effects
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors

Substances

  • Antiviral Agents
  • Pteridines
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase