Discovery of brivanib alaninate ((S)-((R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy)propan-2-yl)2-aminopropanoate), a novel prodrug of dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinase inhibitor (BMS-540215)

被引:120
作者
Cai, Zhen-Wei [1 ]
Zhang, Yongzheng [1 ]
Borzilleri, Robert M. [1 ]
Qian, Ligang [1 ]
Barbosa, Stephanie [1 ]
Wei, Donna [1 ]
Zheng, Xiaoping [1 ]
Wu, Lawrence [1 ]
Fan, Junying [2 ]
Shi, Zhongping [2 ]
Wautlet, Barri S. [3 ]
Mortillo, Steve [3 ]
Jeyaseelan, Robert, Sr. [3 ]
Kukral, Daniel W. [3 ]
Kamath, Amrita [4 ]
Marathe, Punit [4 ]
D'Arienzo, Celia [4 ]
Derbin, George [5 ]
Barrish, Joel C. [1 ]
Robl, Jeffrey A. [1 ]
Hunt, John T. [3 ]
Lombardo, Louis J. [1 ]
Fargnoli, Joseph [3 ]
Bhide, Rajeev S. [1 ]
机构
[1] Bristol Myers Squibb Res & Dev, Dept Chem, Princeton, NJ 08543 USA
[2] Bristol Myers Squibb Res & Dev, Dept Proc Discovery, Princeton, NJ 08543 USA
[3] Bristol Myers Squibb Res & Dev, Dept Discovery Biol, Princeton, NJ 08543 USA
[4] Bristol Myers Squibb Res & Dev, Dept Pharmaceut Candidate Optimizat, Princeton, NJ 08543 USA
[5] Bristol Myers Squibb Res & Dev, Dept Exploratory Biopharm & Stabil, Princeton, NJ 08543 USA
关键词
D O I
10.1021/jm7013309
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of amino acid ester prodrugs of the dual VEGFR-2/FGFR-1 kinase inhibitor 1 (BMS-540215) was prepared in an effort to improve the aqueous solubility and oral bioavailability of the parent compound. These prodrugs were evaluated for their ability to liberate parent drug 1 in in vitro and in vivo systems. The L-alanine prodrug 8 (also known as brivanib alaninate/BMS-582664) was selected as a development candidate and is presently in phase II clinical trials.
引用
收藏
页码:1976 / 1980
页数:5
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