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
書誌事項
- 公開日
- 2013-04
- 権利情報
-
- https://www.elsevier.com/tdm/userlicense/1.0/
- https://www.elsevier.com/legal/tdmrep-license
- DOI
-
- 10.1016/j.bmc.2013.01.074
- 公開者
- Elsevier BV
この論文をさがす
説明
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-phenoxy-imidazo[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%).
収録刊行物
-
- Bioorganic & Medicinal Chemistry
-
Bioorganic & Medicinal Chemistry 21 (8), 2333-2345, 2013-04
Elsevier BV
関連研究データ
もっと見る- Tweet
キーワード
- Male
- Models, Molecular
- Mice, Nude
- Aminoimidazole Carboxamide
- Vascular Endothelial Growth Factor Receptor-2
- Xenograft Model Antitumor Assays
- Rats
- Disease Models, Animal
- Macaca fascicularis
- Mice
- Mice, Inbred AKR
- Human Umbilical Vein Endothelial Cells
- Animals
- Humans
- Pyrazoles
- Female
- Protein Kinase Inhibitors