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

被引：56

作者：

Snow, Roger J.

Abeywardane, Asitha

Campbell, Scot

Lord, John

Kashem, Mohammed A.

Khine, Hnin Hnin

King, Josephine

Kowalski, Jennifer A.

Pullen, Steven S.

Roma, Teresa

Roth, Gregory P.

Sarko, Christopher R.

Wilson, Noel S.

Winters, Michael P.

Wolak, John P.

Cywin, Charles L.

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Med Chem, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Inflammat & Immunol, Ridgefield, CT 06877 USA

[3] Boehringer Ingelheim Pharmaceut Inc, Analyt Sci, Ridgefield, CT 06877 USA

[4] Johnson & Johnson PRD, Exton, PA 19341 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2007年 / 17卷 / 13期

关键词：

D O I：

10.1016/j.bmcl.2007.04.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (c) 2007 Elsevier Ltd. All rights reserved.

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页码：3660 / 3665

页数：6

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