Borzilleri Robert M, Bhide Rajeev S, Barrish Joel C, D'Arienzo Celia J, Derbin George M, Fargnoli Joseph, Hunt John T, Jeyaseelan Robert, Kamath Amrita, Kukral Daniel W, Marathe Punit, Mortillo Steve, Qian Ligang, Tokarski John S, Wautlet Barri S, Zheng Xiaoping, Lombardo Louis J
Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New Jersey 08543-4000, USA.
J Med Chem. 2006 Jun 29;49(13):3766-9. doi: 10.1021/jm060347y.
Substituted 3-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamides were identified as potent and selective inhibitors of vascular endothelial growth factor receptor-2 (VEGFR-2) kinase activity. The enzyme kinetics associated with the VEGFR-2 inhibition of 14 (Ki=49+/-9 nM) confirmed that the aminothiazole-based analogues are competitive with ATP. Analogue 14 demonstrated excellent kinase selectivity, favorable pharmacokinetic properties in multiple species, and robust in vivo efficacy in human lung and colon carcinoma xenograft models.
取代的3-((2-(吡啶-2-基氨基)噻唑-5-基甲基)氨基)苯甲酰胺被鉴定为血管内皮生长因子受体-2（VEGFR-2）激酶活性的强效和选择性抑制剂。与14对VEGFR-2的抑制作用相关的酶动力学（Ki = 49±9 nM）证实，基于氨基噻唑的类似物与ATP具有竞争性。类似物14表现出优异的激酶选择性、在多个物种中良好的药代动力学性质以及在人肺癌和结肠癌异种移植模型中强大的体内疗效。
