Pyrrolo[1,2-b]pyridazin-2-ones as potent inhibitors of HCV NS5B polymerase

Bioorg Med Chem Lett. 2008 Jun 15;18(12):3616-21. doi: 10.1016/j.bmcl.2008.04.066. Epub 2008 May 1.

Abstract

Pyrrolo[1,2-b]pyridazin-2-one analogs were discovered as a novel class of inhibitors of genotype 1 HCV NS5B polymerase. Structure-based design led to the discovery of compound 3 k, which displayed potent inhibitory activities in biochemical and replicon assays (IC(50) (1b)<10nM; EC(50) (1b)=12 nM) as well as good stability towards human liver microsomes (HLM t(1/2)>60 min).

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Binding Sites / drug effects
  • Cell Line
  • Crystallography, X-Ray
  • Humans
  • Hydrogen Bonding
  • Microbial Sensitivity Tests
  • Models, Molecular
  • Molecular Structure
  • Pyridazines / chemical synthesis
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Pyrroles / chemical synthesis
  • Pyrroles / chemistry
  • Pyrroles / pharmacology*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / chemistry

Substances

  • Antiviral Agents
  • Pyridazines
  • Pyrroles
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus