Synthesis and SAR studies of novel heteroaryl fused tetracyclic indole-diamide compounds: potent allosteric inhibitors of the hepatitis C virus NS5B polymerase

Bioorg Med Chem Lett. 2012 Apr 15;22(8):2866-71. doi: 10.1016/j.bmcl.2012.02.063. Epub 2012 Mar 1.

Abstract

Presented here are initial structure-activity relationship (SAR) studies on a series of novel heteroaryl fused tetracyclic indole-based inhibitors of the hepatitis C viral polymerase, NS5B. The introduction of alternative heterocyclic moieties into the indolo-fused inhibitor class significantly expands the reported SAR and resulted in the identification of pyridino analogs, typified by compounds 44 and 45 that displayed excellent potency against the NS5B polymerase of both HCV 1a and HCV 1b genotypes.

MeSH terms

  • Allosteric Regulation
  • Amides / chemistry*
  • Amides / pharmacology
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Hepacivirus / drug effects*
  • Heterocyclic Compounds / chemical synthesis*
  • Heterocyclic Compounds / chemistry*
  • Heterocyclic Compounds / pharmacology
  • Humans
  • Indoles / chemistry
  • Indoles / pharmacology
  • Inhibitory Concentration 50
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*

Substances

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