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
Journal of Medicinal Chemistry2006Vol. 49(13), pp. 3766–3769
Citations Over TimeTop 24% of 2006 papers
R. M. Borzilleri, Rajeev S. Bhide, Joel C. Barrish, Celia D’Arienzo, George Derbin, Joseph Fargnoli, John T. Hunt, Robert Jeyaseelan, Amrita V. Kamath, Daniel Kukral, Punit Marathe, Steve Mortillo, Ligang Qian, John S. Tokarski, Barri Wautlet, Xiaoping Zheng, Louis J. Lombardo
Abstract
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.
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