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)

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 v...

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Veröffentlicht in:	Journal of medicinal chemistry 2008-03, Vol.51 (6), p.1976-1980
Hauptverfasser:	Cai, Zhen-wei, Zhang, Yongzheng, Borzilleri, Robert M, Qian, Ligang, Barbosa, Stephanie, Wei, Donna, Zheng, Xiaoping, Wu, Lawrence, Fan, Junying, Shi, Zhongping, Wautlet, Barri S, Mortillo, Steve, Jeyaseelan, Robert, Kukral, Daniel W, Kamath, Amrita, Marathe, Punit, D’Arienzo, Celia, Derbin, George, Barrish, Joel C, Robl, Jeffrey A, Hunt, John T, Lombardo, Louis J, Fargnoli, Joseph, Bhide, Rajeev S
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Alanine - analogs & derivatives Animals Biological Availability Carcinoma - drug therapy Cell Proliferation - drug effects Clinical Trials, Phase II as Topic Drug Design Drug Evaluation, Preclinical Humans Intestines - drug effects Liver - drug effects Lung Neoplasms - drug therapy Mice Microsomes - drug effects Molecular Structure Prodrugs - chemical synthesis Prodrugs - chemistry Prodrugs - pharmacology Protein Kinase Inhibitors - chemical synthesis Protein Kinase Inhibitors - chemistry Protein Kinase Inhibitors - pharmacology Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Receptor, Fibroblast Growth Factor, Type 1 - antagonists & inhibitors Solubility Stereoisomerism Triazines - chemical synthesis Triazines - chemistry Triazines - pharmacology Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors Water - chemistry Xenograft Model Antitumor Assays
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Zusammenfassung:	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.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm7013309