2. Academic Validation
  3. 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

  • J Med Chem. 2007 Sep 6;50(18):4453-70. doi: 10.1021/jm0611051.
Masaichi Hasegawa 1,  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 Veal,  Mui Cheung
Affiliations

Affiliation

  • 1 Tsukuba Research Laboratories, GlaxoSmithKline K.K., 43 Wadai, Tsukuba, Ibaraki 300-4247, Japan. masaichi.hasegawa@gsk.com
PMID: 17676829 DOI: 10.1021/jm0611051
Abstract

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 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 the N1 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.

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