Discovery of 1H-pyrazol-3(2H)-ones as potent and selective inhibitors of protein kinase R-like endoplasmic reticulum kinase (PERK)

J Med Chem. 2015 Feb 12;58(3):1426-41. doi: 10.1021/jm5017494. Epub 2015 Jan 14.

Abstract

The structure-based design and optimization of a novel series of selective PERK inhibitors are described resulting in the identification of 44 as a potent, highly selective, and orally active tool compound suitable for PERK pathway biology exploration both in vitro and in vivo.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Mice
  • Mice, Nude
  • Models, Molecular
  • Molecular Structure
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship
  • eIF-2 Kinase / antagonists & inhibitors*
  • eIF-2 Kinase / metabolism

Substances

  • Protein Kinase Inhibitors
  • Pyrazoles
  • EIF2AK3 protein, human
  • eIF-2 Kinase