Design and synthesis of brain penetrant selective JNK inhibitors with improved pharmacokinetic properties for the prevention of neurodegeneration

Bioorg Med Chem Lett. 2011 Sep 15;21(18):5521-7. doi: 10.1016/j.bmcl.2011.06.100. Epub 2011 Jul 7.

Abstract

The SAR of a series of brain penetrant, trisubstituted thiophene based JNK inhibitors with improved pharmacokinetic properties is described. These compounds were designed based on information derived from metabolite identification studies which led to compounds such as 42 with lower clearance, greater brain exposure and longer half life compared to earlier analogs.

MeSH terms

  • Animals
  • Brain / metabolism*
  • Chemistry Techniques, Synthetic
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Half-Life
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Nerve Degeneration / prevention & control*
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacokinetics
  • Protein Kinase Inhibitors / pharmacology*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis
  • Thiophenes / chemistry
  • Thiophenes / pharmacokinetics*
  • Thiophenes / pharmacology*

Substances

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