Discovery of thiophene-2-carboxylic acids as potent inhibitors of HCV NS5B polymerase and HCV subgenomic RNA replication. Part 2: tertiary amides

Bioorg Med Chem Lett. 2004 Feb 9;14(3):797-800. doi: 10.1016/j.bmcl.2003.10.068.

Abstract

Further SAR studies on the thiophene-2-carboxylic acids are reported. These studies led to the identification of a series of tertiary amides that show inhibition of both HCV NS5B polymerase in vitro and HCV subgenomic RNA replication in Huh-7 cells. Structural insights about the bioactive conformation of this class of molecules were deduced from a combination of modeling and transferred NOE (trNOE) studies.

MeSH terms

  • Amides / chemistry
  • Amides / pharmacology*
  • Carboxylic Acids
  • Carcinoma, Hepatocellular / chemistry
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / virology
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Genome, Viral
  • Hepacivirus / enzymology*
  • Humans
  • Liver Neoplasms / chemistry
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / virology
  • Magnetic Resonance Spectroscopy
  • Molecular Conformation
  • Molecular Structure
  • RNA, Viral / metabolism*
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors
  • Replicon / drug effects
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Thiophenes / pharmacology*
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Virus Replication / drug effects

Substances

  • Amides
  • Carboxylic Acids
  • Enzyme Inhibitors
  • RNA, Viral
  • Thiophenes
  • Viral Nonstructural Proteins
  • 2-thiophene carboxylic acid
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase