Identification of 1,5-naphthyridine derivatives as a novel series of potent and selective TGF-β type I receptor inhibitors

被引：169

作者：

Gellibert, FO

Woolven, J

Fouchet, MH

Mathews, N

Goodland, H

Lovegrove, V

Laroze, A

Nguyen, VL

Sautet, S

Wang, RL

Janson, C

Smith, W

Krysa, G

Boullay, V

de Gouville, AC

Huet, S

Hartley, D

机构：

[1] GlaxoSmithKline, Dept Med Chem, F-91951 Les Ulis, France

[2] GlaxoSmithKline, Dept Biol, F-91951 Les Ulis, France

[3] GlaxoSmithKline, Discovery Res, Computat & Struct Sci, Stevenage SG1 2NY, Herts, England

[4] GlaxoSmithKline, Dept Med Chem, Stevenage SG1 2NY, Herts, England

[5] GlaxoSmithKline, Discovery Res, Assay Dev & Compound Profiling, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline, Discovery Res, King Of Prussia, PA 19406 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2004年 / 47卷 / 18期

关键词：

D O I：

10.1021/jm0400247

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Optimization of the screening hit 1 led to the identification of novel 1,5-naphthyridine aminothiazole and pyrazole derivatives, which are potent and selective inhibitors of the transforming growth factor-beta type I receptor, ALK5. Compounds 15 and 19, which inhibited ALK5 autophosphorylation with IC50 = 6 and 4 nM, respectively, showed potent activities in both binding and cellular assays and exhibited selectivity over p38 mitogen-activated protein kinase. The X-ray crystal structure of 19 in complex with human ALK5 is described, confirming the binding mode proposed from docking studies.

引用

页码：4494 / 4506

页数：13

共 28 条

[1] TGF-β signaling in cancer -: a double-edged sword [J].