Highly selective c-Jun N-terminal kinase (JNK) 3 inhibitors with in vitro CNS-like pharmacokinetic properties II. Central core replacement

Bioorg Med Chem Lett. 2011 Jun 15;21(12):3726-9. doi: 10.1016/j.bmcl.2011.04.074. Epub 2011 Apr 27.

Abstract

In this Letter, we describe the evolution of selective JNK3 inhibitors from 1, that routinely exhibit >10-fold selectivity over JNK1 and >1000-fold selectivity over related MAPKs. Strong SAR was found for substitution of the naphthalene ring, as well as for inhibitors adopting different central scaffolds. Significant potency gains were appreciated by inverting the polarity of the thione of the parent triazolothione 1, resulting in potent compounds with attractive pharmacokinetic profiles.

MeSH terms

  • Animals
  • Cells, Cultured
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / enzymology
  • Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
  • Molecular Structure
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / chemistry
  • Naphthalenes / pharmacology
  • Solubility
  • Structure-Activity Relationship
  • Thiones / chemical synthesis*
  • Thiones / chemistry
  • Thiones / pharmacology

Substances

  • Enzyme Inhibitors
  • Naphthalenes
  • Thiones
  • naphthalene
  • Mitogen-Activated Protein Kinase 10