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

Adrian L Smith; Kristin L Andrews; Holger Beckmann; Steven F Bellon; Pedro J Beltran; Shon Booker; Hao Chen; Young-Ah Chung; Noel D D'Angelo; Jennifer Dao; Kenneth R Dellamaggiore; Peter Jaeckel; Richard Kendall; Katja Labitzke; Alexander M Long; Silvia Materna-Reichelt; Petia Mitchell; Mark H Norman; David Powers; Mark Rose; Paul L Shaffer; Michelle M Wu; J Russell Lipford

doi:10.1021/jm5017494

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.

Affiliation

¹ Departments of †Medicinal Chemistry, ‡Molecular Structure and Characterization, §Oncology Research, and ∥Pharmacokinetics and Drug Metabolism, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.

PMID: 25587754
DOI: 10.1021/jm5017494

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