Discovery of novel Benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors
Discovery of novel Benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors
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DOI：
10.1021/jm0611051
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发表时间：
2007-09-06
影响因子：
7.3
通讯作者：
Cheung, Mui
中科院分区：
文献类型：
--
作者：
Hasegawa, Masaichi;Nishigaki, Naohiko;Cheung, Mui
我们在这里披露了一个新型的化学化学系列苯咪唑 - 尿素作为VEGFR-2和TIE-2激酶受体的抑制剂，两者都与血管生成有关。结构 - 活性关系（SAR）研究阐明了苯二唑唑（段E）和尿素（段B）部分的氮氮的关键作用。当苯二唑 - 尿素化合物与VEGFR-2酶结合时，还通过X射线晶体学阐明Ni氮和尿素部分的作用来支持SAR结果。左侧苯环（段A）占据了背口，其中3-氢磷酸化取代基受到TIE-2活性的青睐。
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.