Design and synthesis of disubstituted thiophene and thiazole based inhibitors of JNK

Bioorg Med Chem Lett. 2010 Dec 15;20(24):7303-7. doi: 10.1016/j.bmcl.2010.10.066. Epub 2010 Oct 21.

Abstract

From high throughput screening, we discovered compound 1, the prototype for a series of disubstituted thiophene inhibitors of JNK which is selective towards closely related MAP kinases p38 and Erk2. Herein we describe the evolution of these compounds to a novel class of thiophene and thiazole JNK inhibitors that retain favorable solubility, permeability, and P-gp properties for development as CNS agents for treatment of neurodegeneration. Compound 61 demonstrated JNK3 IC(50)=77 nM and retained the excellent broad kinase selectivity observed for the series.

MeSH terms

  • Animals
  • Drug Design
  • Humans
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Microsomes, Liver / metabolism
  • Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 10 / metabolism
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Quinolines / chemical synthesis*
  • Quinolines / chemistry
  • Quinolines / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry*
  • Thiazoles / pharmacology
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry*
  • Thiophenes / pharmacology

Substances

  • Protein Kinase Inhibitors
  • Quinolines
  • Thiazoles
  • Thiophenes
  • Mitogen-Activated Protein Kinase 10
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 8