Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus

Bioorg Med Chem Lett. 2011 May 15;21(10):2925-9. doi: 10.1016/j.bmcl.2011.03.067. Epub 2011 Mar 23.

Abstract

Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 μM, %F=18), are reported.

MeSH terms

  • Drug Design
  • Enzyme Activation / drug effects*
  • Hepacivirus / enzymology*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry
  • Heterocyclic Compounds / pharmacology*
  • Indoles / chemistry*
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Structure
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

  • Heterocyclic Compounds
  • Indoles
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus