Discovery of 3-(2,6-Dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea (NVP-BGJ398), A Potent and Selective Inhibitor of the Fibroblast Growth Factor Receptor Family of Receptor Tyrosine Kinase

被引：396

作者：

Guagnano, Vito ^{[1
]}

Furet, Pascal ^{[1
]}

Spanka, Carsten ^{[1
]}

Bordas, Vincent ^{[1
]}

Le Douget, Mickael ^{[1
]}

Stamm, Christelle ^{[1
]}

Brueggen, Josef ^{[1
]}

Jensen, Michael R. ^{[1
]}

Schnell, Christian ^{[1
]}

Schmid, Herbert ^{[1
]}

Wartmann, Markus ^{[1
]}

Berghausen, Joerg ^{[1
]}

Drueckes, Peter ^{[1
]}

Zimmerlin, Alfred ^{[1
]}

Bussiere, Dirksen ^{[1
]}

Murray, Jeremy ^{[1
]}

Porta, Diana Graus ^{[1
]}

机构：

[1] Novartis Inst BioMed Res, CH-4002 Basel, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2011年 / 54卷 / 20期

关键词：

HUMAN BREAST; MULTIPLE-MYELOMA; MYELOPROLIFERATIVE SYNDROME; ONCOGENE AMPLIFICATION; ACTIVATING MUTATIONS; GENE AMPLIFICATION; FGF FAMILY; INT-2; GENE; EXPRESSION; CANCER;

D O I：

10.1021/jm2006222

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of N-aryl-N'-pyrimidin-4-yl ureas has been optimized to afford potent and selective inhibitors of the fibroblast growth factor receptor tyrosine kinases 1, 2, and 3 by rationally designing the substitution pattern of the aryl ring. On the basis of its in vitro profile, compound 1h (NVP-BGJ398) was selected for in vivo evaluation and showed significant antitumor activity in RT112 bladder cancer xenografts models overexpressing wild-type FGFR3. These results support the potential therapeutic use of 1h as a new anticancer agent.

引用

页码：7066 / 7083

页数：18