Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 20, Issue 24, Pages 7051-7058Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2012.10.004
Keywords
VEGF; VEGFR2; Kinase inhibitor; Imidazo[1,2-b]pyridazine
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The vascular endothelial growth factor (VEGF) signaling pathway has been implicated in tumor angiogenesis, and inhibition of the VEGF pathway is considered an efficacious method for treating cancer. Herein, we describe synthetic studies of imidazo[1,2-b]pyridazine derivatives as VEGF receptor 2 (VEGFR2) kinase inhibitors. The imidazo[1,2-b]pyridazine scaffold was designed and synthesized as a hinge binder according to the previously reported crystal structure of pyrrolo[3,2-d]pyrimidine 1 with VEGFR2. Structure-activity relationship studies revealed that meta-substituted 6-phenoxy-imidazo[1,2-b]pyridazine derivatives had potent affinity for VEGFR2. In particular, N-[3-(imidazo[1,2-b]pyridazin-6-yloxy)phenyl]-3-(trifluoromethyl) benzamide (6b) exhibited strong inhibitory activity against VEGFR2 with an IC50 value of 7.1 nM, and it inhibited platelet-derived growth factor receptor beta kinase with an IC50 value of 15 nM. (C) 2012 Elsevier Ltd. All rights reserved.
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