Structure-based design of a novel series of azetidine inhibitors of the hepatitis C virus NS3/4A serine protease

Bioorg Med Chem Lett. 2014 Sep 15;24(18):4444-4449. doi: 10.1016/j.bmcl.2014.08.002. Epub 2014 Aug 9.

Abstract

Structural homology between thrombin inhibitors and the early tetrapeptide HCV protease inhibitor led to the bioisosteric replacement of the P2 proline by a 2,4-disubstituted azetidine within the macrocyclic β-strand mimic. Molecular modeling guided the design of the series. This approach was validated by the excellent activity and selectivity in biochemical and cell based assays of this novel series and confirmed by the co-crystal structure of the inhibitor with the NS3/4A protein (PDB code: 4TYD).

Keywords: HCV NS3/4A protease inhibitors; Hepatitis C; Macrocycle.

MeSH terms

  • Azetidines / chemical synthesis
  • Azetidines / chemistry
  • Azetidines / pharmacology*
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Models, Molecular
  • Molecular Structure
  • Serine Proteinase Inhibitors / chemical synthesis
  • Serine Proteinase Inhibitors / chemistry
  • Serine Proteinase Inhibitors / pharmacology*
  • Structure-Activity Relationship
  • Viral Nonstructural Proteins / antagonists & inhibitors*
  • Viral Nonstructural Proteins / metabolism

Substances

  • Azetidines
  • NS3 protein, hepatitis C virus
  • NS4 protein, hepatitis C virus
  • Serine Proteinase Inhibitors
  • Viral Nonstructural Proteins
  • azetidine