Bicyclic octahydrocyclohepta[b]pyrrol-4(1H)one Derivatives as Novel Selective Anti-Hepatitis C Virus Agents

Eur J Med Chem. 2016 Oct 21;122:319-325. doi: 10.1016/j.ejmech.2016.06.041. Epub 2016 Jun 23.

Abstract

We report the discovery of the bicyclic octahydrocyclohepta[b]pyrrol-4(1H)-one scaffold as a new chemotype with anti-HCV activity on genotype 1b and 2a subgenomic replicons. The most potent compound 34 displayed EC50 values of 1.8 μM and 4.5 μM in genotype 1b and 2a, respectively, coupled with the absence of any antimetabolic effect (gt 1b SI = 112.4; gt 2a SI = 44.2) in a cell-based assay. Compound 34 did not target HCV NS5B, IRES, NS3 helicase, or selected host factors, and thus future work will involve the unique mechanism of action of these new antiviral compounds.

Keywords: Anti-HCV agents; Aza-Cope–Mannich reaction; HCV inhibitors; Hepatitis C virus; Octahydrocyclohepta[b]pyrrol-4(1H)one derivatives.

MeSH terms

  • Antiviral Agents / chemistry*
  • Antiviral Agents / pharmacology*
  • Bridged Bicyclo Compounds, Heterocyclic / chemistry*
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
  • Cell Line
  • Genotype
  • Hepacivirus / drug effects*
  • Hepacivirus / genetics
  • Hepacivirus / physiology
  • Humans
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Bridged Bicyclo Compounds, Heterocyclic