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

Kevin J Moriarty; Hidenori Takahashi; Steven S Pullen; Hnin Hnin Khine; Rosemarie H Sallati; Ernest L Raymond; Joseph R Woska Jr; Deborah D Jeanfavre; Gregory P Roth; Michael P Winters; Lei Qiao; Declan Ryan; Renee DesJarlais; Darius Robinson; Matthew Wilson; Mark Bobko; Brian N Cook; Ho Yin Lo; Peter A Nemoto; Mohammed A Kashem; John P Wolak; André White; Ronald L Magolda; Bruce Tomczuk

doi:10.1016/j.bmcl.2008.09.015

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.

Affiliation

¹ Johnson & Johnson, PRDUS, LLC, Springhouse, PA 19477, USA.

PMID: 18819799
DOI: 10.1016/j.bmcl.2008.09.015

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