1-Aryl-3,4-dihydroisoquinoline inhibitors of JNK3

Bioorg Med Chem Lett. 2009 Apr 15;19(8):2230-4. doi: 10.1016/j.bmcl.2009.02.098. Epub 2009 Feb 28.

Abstract

A series of 1-aryl-3,4-dihydroisoquinoline inhibitors of JNK3 are described. Compounds 20 and 24 are the most potent inhibitors (pIC50 7.3 and 6.9, respectively in a radiometric filter binding assay), with 10- and 1000-fold selectivity over JNK2 and JNK1, respectively, and selectivity within the wider mitogen-activated protein kinase (MAPK) family against p38alpha and ERK2. X-ray crystallography of 16 reveals a highly unusual binding mode where an H-bond acceptor interaction with the hinge region is made by a chloro substituent.

Publication types

  • Comparative Study

MeSH terms

  • Binding Sites / physiology
  • Fluorescence Polarization / methods
  • Humans
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology
  • Mitogen-Activated Protein Kinase 10 / antagonists & inhibitors*
  • Mitogen-Activated Protein Kinase 10 / metabolism
  • Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 14 / metabolism
  • Mitogen-Activated Protein Kinase 8 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / metabolism
  • Protein Kinase Inhibitors / pharmacology

Substances

  • G 1617
  • Isoquinolines
  • Protein Kinase Inhibitors
  • Mitogen-Activated Protein Kinase 10
  • Mitogen-Activated Protein Kinase 14
  • Mitogen-Activated Protein Kinase 8