GSK2578215A; A potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor

被引：128

作者：

Reith, Alastair D. ^{[1
]}

Bamborough, Paul ^{[2
]}

Jandu, Karamjit

Andreotti, Daniele

Mensah, Lucy ^{[2
]}

Dossang, Pamela ^{[2
]}

Choi, Hwan Geun ^{[3
,4
]}

Deng, Xianming ^{[3
,4
]}

Zhang, Jinwei ^{[5
]}

Alessi, Dario R. ^{[5
]}

Gray, Nathanael S. ^{[3
,4
]}

机构：

[1] GlaxoSmithKline Pharmaceut R&D, R&D China, External Alliances & Dev, Stevenage, Herts, England

[2] GlaxoSmithKline Pharmaceut R&D, Platform Technol Sci, Stevenage, Herts, England

[3] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA

[5] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2012年 / 22卷 / 17期

基金：

英国医学研究理事会;

关键词：

LRRK2; Drug discovery; Kinase inhibitors; Parkinson's disease; PARKINSONS-DISEASE;

D O I：

10.1016/j.bmcl.2012.06.104

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Leucine-rich repeat kinase 2 (LRRK2) is a promising therapeutic target for some forms of Parkinson's disease. Here we report the discovery and characterization of 2-arylmethyloxy-5-subtitutent-N-arylbenzamides with potent LRRK2 activities exemplified by GSK2578215A which exhibits biochemical IC(50)s of around 10 nM against both wild-type LRRK2 and the G2019S mutant. GSK2578215A exhibits exceptionally high selectivity for LRRK2 across the kinome, substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.3-1.0 mu M in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100 mg/kg. (C) 2012 Elsevier Ltd. All rights reserved.

引用

页码：5625 / 5629

页数：5

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