Discovery and evaluation of N-cyclopropyl-2,4-difluoro-5-((2-(pyridin-2-ylamino)thiazol-5-ylmethyl)amino)benzamide (BMS-605541), a selective and orally efficacious inhibitor of vascular endothelial growth factor receptor-2

被引：44

作者：

Borzilleri, Robert M. ^{[1
]}

Bhide, Rajeev S. ^{[1
]}

Barrish, Joel C. ^{[1
]}

D'Arienzo, Celia J. ^{[1
]}

Derbin, George M. ^{[1
]}

Fargnoli, Joseph ^{[1
]}

Hunt, John T. ^{[1
]}

Jeyaseelan, Robert, Sr. ^{[1
]}

Kamath, Amrita ^{[1
]}

Kukral, Daniel W. ^{[1
]}

Marathe, Punit ^{[1
]}

Mortillo, Steve ^{[1
]}

Qian, Ligang ^{[1
]}

Tokarski, John S. ^{[1
]}

Wautlet, Barri S. ^{[1
]}

Zheng, Xiaoping ^{[1
]}

Lombardo, Louis J. ^{[1
]}

机构：

[1] Bristol Myers Squibb Co, Pharmaceut Res Inst, Princeton, NJ 08543 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2006年 / 49卷 / 13期

关键词：

D O I：

10.1021/jm060347y

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 (K-i=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.

引用

页码：3766 / 3769

页数：4

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