Synthesis and SAR of novel isoxazoles as potent c-jun N-terminal kinase (JNK) inhibitors

Bioorg Med Chem Lett. 2014 Jan 1;24(1):161-4. doi: 10.1016/j.bmcl.2013.11.052. Epub 2013 Dec 4.

Abstract

The design and synthesis of isoxazole 3 is described, a potent JNK inhibitor with two fold selectivity over p38. Optimization of this scaffold led to compounds 27 and 28 which showed greatly improved selectivity over p38 by maintaining the JNK3 potency of compound 3. Extensive SAR studies will be described as well as preliminary in vivo data of the two lead compounds.

Keywords: Isoxazole; JNK; Kinase; c-Jun.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Administration, Oral
  • Animals
  • Dose-Response Relationship, Drug
  • Humans
  • Isoxazoles / administration & dosage
  • Isoxazoles / chemical synthesis
  • Isoxazoles / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Molecular Structure
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemical synthesis
  • Protein Kinase Inhibitors / pharmacology*
  • Rats
  • Structure-Activity Relationship
  • Tissue Distribution

Substances

  • Isoxazoles
  • Protein Kinase Inhibitors
  • JNK Mitogen-Activated Protein Kinases