Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): optimization for JNK potency and physicochemical properties

Bioorg Med Chem Lett. 2013 Jun 15;23(12):3565-9. doi: 10.1016/j.bmcl.2013.04.029. Epub 2013 Apr 21.

Abstract

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC50 of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.

Publication types

  • Letter

MeSH terms

  • Crystallography, X-Ray
  • Indazoles / chemistry
  • Indazoles / pharmacology
  • Indoles / chemistry*
  • Indoles / pharmacology*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors*
  • JNK Mitogen-Activated Protein Kinases / chemistry
  • Phosphorylation
  • Protein Kinase Inhibitors / chemistry*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrimidines / chemistry*
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Indoles
  • Protein Kinase Inhibitors
  • Pyrimidines
  • JNK Mitogen-Activated Protein Kinases