Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors
DOI: 10.1016/j.bmcl.2007.04.045
Title: Hit-to-lead studies on benzimidazole inhibitors of ITK: Discovery of a novel class of kinase inhibitors
Journal Title: Bioorganic & Medicinal Chemistry Letters
Volume: 17
Issue: 13
Publication Date: 1 July 2007
Start Page: 3660
End Page: 3665
Published online: online 25 April 2007
ISSN: 0960-894X
Affiliations:

  • a Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA

  • b Inflammation and Immunology, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA

  • c Analytical Sciences, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA

  • d Johnson and Johnson PRD, 665 Stockton Drive, Exton, PA 19341, USA
  • Abstract: azole 1 was identified as a selective inhibitor of ITK by high throughput screening. Hit-to-lead studies defined the SAR at all three substituents. Reversing the amide linkage at C6 led to 16, with a fivefold improvement of potency. This enhancement is rationalized by the conformational preference of the substituent. A model for the binding of the benzimidazoles to the ATP-binding site of ITK is proposed.
    Accepted: 16 April 2007
    Received: 9 February 2007
    Revised: 6 April 2007
    Keywords: ITK; Kinase; Kinase inhibitor; Benzimidazole; Inducible T cell kinase
    Tel: +1 203 798 4060
    Fax: +1 203 798 5297
    Email: rsnow@rdg.boehringer

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