Discovery of Novel Benzimidazoles as Potent Inhibitors of TIE-2 and VEGFR-2 Tyrosine Kinase Receptors
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- 作者：Masaichi Hasegawa ; Naohiko Nishigaki ; Yoshiaki Washio ; Kazuya Kano ; Philip A. Harris ; Hideyuki Sato ; Ichiro Mori ; Rob I. West ; Megumi Shibahara ; Hiroko Toyoda ; Liping Wang ; Robert T. Nolte ; James M. V
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：September 6, 2007
- 年：2007
- 卷：50
- 期：18
- 页码：4453 - 4470
- 全文大小：324K
- 年卷期：v.50,no.18(September 6, 2007)
- ISSN：1520-4804
文摘
We herein disclose a novel chemical series of benzimidazole-ureas as inhibitors of VEGFR-2 and TIE-2kinase receptors, both of which are implicated in angiogenesis. Structure-activity relationship (SAR) studieselucidated a critical role for the N1 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 theN1 nitrogen and the urea moiety when the benzimidazole-urea compounds were bound to the VEGFR-2enzyme. The left side phenyl ring (segment A) occupies the backpocket where a 3-hydrophobic substituentwas favored for TIE-2 activity.