1,5-Benzodiazepine inhibitors of HCV NS5B polymerase

Bioorg Med Chem Lett. 2009 May 1;19(9):2492-6. doi: 10.1016/j.bmcl.2009.03.035. Epub 2009 Mar 14.

Abstract

Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC(50)=400nM and 270nM, respectively) and selective (CC(50)>20muM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.

MeSH terms

  • Acrylates / chemistry
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Benzodiazepines / chemistry*
  • Chemistry, Pharmaceutical / methods*
  • Crystallography, X-Ray
  • Drug Design
  • Hepacivirus / enzymology
  • Hepacivirus / metabolism*
  • Humans
  • Inhibitory Concentration 50
  • Models, Chemical
  • Molecular Structure
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Acrylates
  • Antiviral Agents
  • Viral Nonstructural Proteins
  • Benzodiazepines
  • NS-5 protein, hepatitis C virus
  • acrylic acid