Discovery of novel Benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors

被引：202

作者：

Hasegawa, Masaichi

Nishigaki, Naohiko

Washio, Yoshiaki

Kano, Kazuya

Harris, Philip A.

Sato, Hideyuki

Mori, Ichiro

West, Rob I.

Shibahara, Megumi

Toyoda, Hiroko

Wang, Liping

Nolte, Robert T.

Veal, James M.

Cheung, Mui

机构：

[1] GlaxoSmithKline KK, Tsukuba Res Labs, Tsukuba, Ibaraki 3004247, Japan

[2] GlaxoSmithKline Inc, Res Triangle Pk, NC 27709 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 18期

关键词：

D O I：

10.1021/jm0611051

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2 kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studies elucidated a critical role for the NI nitrogen of both the benzimidazole (segment E) and urea (segment B) moieties. The SAR results were also supported by the X-ray crystallographic elucidation of the role of the NI nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2 enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituent was favored for TIE-2 activity.

引用

页码：4453 / 4470

页数：18

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