Discovery, SAR and X-ray structure of 1H-benzimidazole-5-carboxylic acid cyclohexyl-methyl-amides as inhibitors of inducible T-cell kinase (Itk)

Bioorg Med Chem Lett. 2008 Oct 15;18(20):5545-9. doi: 10.1016/j.bmcl.2008.09.015. Epub 2008 Sep 7.

Abstract

A series of novel potent benzimidazole based inhibitors of interleukin-2 T-cell kinase (Itk) were prepared. In this report, we discuss the structure-activity relationship (SAR), selectivity, and cell-based activity for the series. We also discuss the SAR associated with an X-ray structure of one of the small-molecule inhibitors bound to ITK.

MeSH terms

  • Amides / chemistry*
  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry*
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry*
  • Chemistry, Pharmaceutical / methods*
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Inhibitory Concentration 50
  • Mice
  • Microsomes, Liver / metabolism*
  • Models, Chemical
  • Molecular Conformation
  • Protein-Tyrosine Kinases / chemistry*
  • Structure-Activity Relationship

Substances

  • 5-benzimidazolecarboxylic acid
  • Amides
  • Benzimidazoles
  • Carboxylic Acids
  • Enzyme Inhibitors
  • Protein-Tyrosine Kinases
  • emt protein-tyrosine kinase