Discovery of novel benzimidazoles as potent inhibitors of TIE-2 and VEGFR-2 tyrosine kinase receptors.
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.
Hasegawa
Masaichi
M
Tsukuba Research Laboratories, GlaxoSmithKline K.K., 43 Wadai, Tsukuba, Ibaraki 300-4247, Japan. masaichi.hasegawa@gsk.com
Nishigaki
Naohiko
N
Washio
Yoshiaki
Y
Kano
Kazuya
K
Harris
Philip A
PA
Sato
Hideyuki
H
Mori
Ichiro
I
West
Rob I
RI
Shibahara
Megumi
M
Toyoda
Hiroko
H
Wang
Liping
L
Nolte
Robert T
RT
Veal
James M
JM
Cheung
Mui
M
D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D010766:Phosphorylation; D042787:Receptor, TIE-2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001562:Benzimidazoles; D042787:Receptor, TIE-2; D040301:Vascular Endothelial Growth Factor Receptor-2