Synthesis and biological evaluation of novel (4 or 5-aryl)pyrazolyl-indoles as inhibitors of interleukin-2 inducible T-cell kinase (ITK)

Bioorg Med Chem. 2010 Jun 15;18(12):4547-59. doi: 10.1016/j.bmc.2010.04.056. Epub 2010 Apr 24.

Abstract

Interleukin-2 inducible T-cell kinase (ITK) is one of five kinases that belong to the Tec kinase family that plays an important role in T-cell and mast cell signaling. Various reports point to a role of ITK in the treatment of allergic asthma. For example, it was shown that mice lacking ITK have reduced airway hyperresponsiveness, inflammation and tracheal responses in an allergic asthma model. In this article, we disclose novel ITK inhibitors based on (4 or 5-aryl)pyrazolyl-indole scaffold that were also found to be selective for ITK over other kinases like IRK, CDK2, GSK3ss and PKA.

MeSH terms

  • Animals
  • Asthma / drug therapy
  • Binding Sites
  • Computer Simulation
  • Disease Models, Animal
  • Indoles / chemical synthesis
  • Indoles / chemistry*
  • Indoles / therapeutic use
  • Mice
  • Models, Molecular
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / therapeutic use
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Protein-Tyrosine Kinases / metabolism
  • Structure-Activity Relationship

Substances

  • Indoles
  • Protein Kinase Inhibitors
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase