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

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 06期

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

页码：1976 / 1980

页数：5

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