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Bioorg Med Chem Lett. 2007 Jul 1;17(13):3660-5. Epub 2007 Apr 25.

Hit-to-lead studies on benzimidazole inhibitors of ITK: discovery of a novel class of kinase inhibitors.

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1
Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA. rsnow@rdg.boehringer-ingelheim.com <rsnow@rdg.boehringer-ingelheim.com>

Abstract

Benzimidazole 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.

PMID:
17499505
DOI:
10.1016/j.bmcl.2007.04.045
[Indexed for MEDLINE]
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