N-Acetamideindolecarboxylic acid allosteric 'finger-loop' inhibitors of the hepatitis C virus NS5B polymerase: discovery and initial optimization studies

Bioorg Med Chem Lett. 2010 Feb 1;20(3):857-61. doi: 10.1016/j.bmcl.2009.12.101. Epub 2010 Jan 4.

Abstract

SAR studies at the N(1)-position of allosteric indole-based HCV NS5B inhibitors has led to the discovery of acetamide derivatives with good cellular potency in subgenomic replicons (EC(50) <200 nM). This class of inhibitors displayed improved physicochemical properties and favorable ADME-PK profiles over previously described analogs in this class.

Publication types

  • Comparative Study

MeSH terms

  • Acetamides / chemistry*
  • Acetamides / pharmacology
  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / pharmacology
  • Caco-2 Cells
  • Carboxylic Acids / chemistry*
  • Carboxylic Acids / pharmacology
  • Cell Line
  • DNA-Directed RNA Polymerases / antagonists & inhibitors
  • DNA-Directed RNA Polymerases / metabolism
  • Drug Discovery* / methods
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology*
  • Humans
  • Microsomes, Liver / enzymology
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / metabolism
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Acetamides
  • Antiviral Agents
  • Carboxylic Acids
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase
  • DNA-Directed RNA Polymerases