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.
Subject(s)
Benzimidazoles/chemical synthesis , Models, Molecular , Receptor, TIE-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites , Crystallography, X-Ray , Humans , Mice , Molecular Structure , NIH 3T3 Cells , Phosphorylation , Receptor, TIE-2/metabolism , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/chemistryABSTRACT
A novel series of anilinopyrazoles has been designed based on the X-ray crystal structure analysis. Most compounds from this series not only show sub-nanomolar IC(50) values for CDK2, but also demonstrate almost 1000-fold selectivity to other kinases including CDK1.
