Discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2 -methylphenyl]-1,3-dimethyl-1H-pyrazole-5-carboxamide (TAK-593), a highly potent VEGFR2 kinase inhibitor

作者：Miyamoto Naoki; Sakai Nozomu; Hirayama Takaharu; Miwa Kazuhiro; Oguro Yuya; Oki Hideyuki; Okada Kengo; Takagi Terufumi; Iwata Hidehisa; Awazu Yoshiko; Yamasaki Seiji; Takeuchi Toshiyuki; Miki Hiroshi; Hori Akira; Imamura Shinichi^*

来源：Bioorganic & Medicinal Chemistry, 2013, 21(8): 2333-2345.

DOI：10.1016/j.bmc.2013.01.074

• VEGF
• VEGFR2
• Kinase inhibitor
• Imidazo[1,2-b]pyridazine

Vascular endothelial growth factor (VEGF) plays important roles in tumor angiogenesis, and the inhibition of its signaling pathway is considered an effective therapeutic option for the treatment of cancer. In this study, we describe the design, synthesis, and biological evaluation of 2-acylamino-6-phenoxyimidazo[1,2-b]pyridazine derivatives. Hybridization of two distinct imidazo[1,2-b]pyridazines 1 and 2, followed by optimization led to the discovery of N-[5-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)-2-methylphenyl]-1,3-dimethyl- 1H-pyrazole-5-carboxamide (23a, TAK-593) as a highly potent VEGF receptor 2 kinase inhibitor with an IC50 value of 0.95 nM. The compound 23a strongly suppressed proliferation of VEGF-stimulated human umbilical vein endothelial cells with an IC50 of 0.30 nM. Kinase selectivity profiling revealed that 23a inhibited platelet-derived growth factor receptor kinases as well as VEGF receptor kinases. Oral administration of 23a at 1 mg/kg bid potently inhibited tumor growth in a mouse xenograft model using human lung adenocarcinoma A549 cells (T/C = 8%).

• 出版日期2013-4-15