کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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1359497 | 1500521 | 2012 | 8 صفحه PDF | دانلود رایگان |
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 β kinase with an IC50 value of 15 nM.
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Journal: Bioorganic & Medicinal Chemistry - Volume 20, Issue 24, 15 December 2012, Pages 7051–7058