Design and synthesis of lactam-thiophene carboxylic acids as potent hepatitis C virus polymerase inhibitors

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3979-85. doi: 10.1016/j.bmcl.2014.06.031. Epub 2014 Jun 20.

Abstract

Herein we report the successful incorporation of a lactam as an amide replacement in the design of hepatitis C virus NS5B Site II thiophene carboxylic acid inhibitors. Optimizing potency in a replicon assay and minimizing potential risk for CYP3A4 induction led to the discovery of inhibitor 22a. This lead compound has a favorable pharmacokinetic profile in rats and dogs.

Keywords: CYP induction; HCV; Lactam; NS5B polymerase; PXR; Thiophene.

MeSH terms

  • Animals
  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology
  • Lactams / chemistry
  • Molecular Structure
  • RNA-Dependent RNA Polymerase / antagonists & inhibitors*
  • RNA-Dependent RNA Polymerase / metabolism
  • Rats
  • Structure-Activity Relationship
  • Thiophenes / chemistry
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Antiviral Agents
  • Carboxylic Acids
  • Enzyme Inhibitors
  • Lactams
  • Thiophenes
  • Viral Nonstructural Proteins
  • NS-5 protein, hepatitis C virus
  • RNA-Dependent RNA Polymerase