Pyrrolidine-5,5-trans-lactams. 4. Incorporation of a P3/P4 urea leads to potent intracellular inhibitors of hepatitis C virus NS3/4A protease

Org Lett. 2003 Nov 27;5(24):4627-30. doi: 10.1021/ol035826v.

Abstract

[reaction: see text] In this, the first of two Letters, we describe how a P3/P4 urea linking unit was used to greatly enhance the biochemical and replicon potency of inhibitors based upon the pyrrolidine-5,5-trans-lactam template. Compound 7b demonstrated a 100 nM IC(50) in the replicon cell-based surrogate HCV assay.

MeSH terms

  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Crystallography, X-Ray
  • Hepacivirus / drug effects
  • Hepacivirus / enzymology*
  • Hepacivirus / physiology
  • Inhibitory Concentration 50
  • Lactams / chemistry*
  • Molecular Conformation
  • Molecular Structure
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Pyrrolidines / chemistry*
  • Urea / chemistry*
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Lactams
  • NS3 protein, hepatitis C virus
  • Protease Inhibitors
  • Pyrrolidines
  • Viral Nonstructural Proteins
  • Urea
  • pyrrolidine