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

• Published in: Bioorganic & medicinal chemistry Vol. 18; no. 20; pp. 5545 - 5549
• Main Authors: MORIARTY, Kevin J, TAKAHASHI, Hidenori, LEI QIAO, RYAN, Declan, DESJARLAIS, Renee, ROBINSON, Darius, WILSON, Matthew, BOBKO, Mark, COOK, Brian N, HO YIN LO, NEMOTO, Peter A, KASHEM, Mohammed A, PULLEN, Steven S, WOLAK, John P, WHITE, André, MAGOLDA, Ronald L, TOMCZUK, Bruce, HNIN HNIN KHINE, SALLATI, Rosemarie H, RAYMOND, Ernest L, WOSKA, Joseph R, JEANFAVRE, Deborah D, ROTH, Gregory P, WINTERS, Michael P
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier 15.10.2008
• Subjects: Amides - chemistry; Animals; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Carboxylic Acids - chemical synthesis; Carboxylic Acids - chemistry; Chemistry, Pharmaceutical - methods; Crystallography, X-Ray; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Immunomodulators; Inhibitory Concentration 50; Medical sciences; Mice; Microsomes, Liver - metabolism; Models, Chemical; Molecular Conformation; Pharmacology. Drug treatments; Protein-Tyrosine Kinases - chemistry; Structure-Activity Relationship; Itk; Cyclohexane derivatives; Nitrile; Nitrogen heterocycle; SAR; Liver; Selectivity; Microsome; Modeling; Signal transduction; Structure activity relation; Benzimidazole; Molecular model; Bicyclic compound; Aromatic compound; Chemical synthesis; Enzyme; Transferases; Enzyme inhibitor; Inhibitor enzyme complex; In vitro; Immunomodulator; Metabolic stability; Carboxamide; Benzamide derivatives; Inhibitor
• ISSN: 0960-894X; 0968-0896; 1464-3405; 1464-3391
• DOI: 10.1016/j.bmcl.2008.09.015

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.