Design, synthesis, and evaluation of imidazo[1,2-b]pyridazine derivatives having a benzamide unit as novel VEGFR2 kinase inhibitors

• Published in: Bioorganic & medicinal chemistry 2012-12, Vol.20 (24), p.7051-7058
• Main Authors: Miyamoto, Naoki, Oguro, Yuya, Takagi, Terufumi, Iwata, Hidehisa, Miki, Hiroshi, Hori, Akira, Imamura, Shinichi
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Benzamides - chemical synthesis; Benzamides - chemistry; Benzamides - pharmacology; Biological and medical sciences; Cell Line, Tumor; Drug Design; General pharmacology; Humans; Imidazo[1,2-b]pyridazine; Imidazoles - chemical synthesis; Imidazoles - chemistry; Imidazoles - pharmacology; Kinase inhibitor; Male; Medical sciences; Mice; Models, Molecular; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Prostatic Neoplasms - drug therapy; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGF; VEGFR2; Xenograft Model Antitumor Assays
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.10.004

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 7.1nM, and it inhibited platelet-derived growth factor receptor β kinase with an IC50 value of 15nM.