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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Reith, Alastair D.¹  Bamborough, Paul²  Mensah, Lucy²  Dossang, Pamela²  Choi, Hwan Geun^3,4  Deng, Xianming^3,4  Zhang, Jinwei⁵  Alessi, Dario R.⁵  Gray, Nathanael S.^3,4 

[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

关键词: LRRK2;    Drug discovery;    Kinase inhibitors;    Parkinson's disease;   

DOI  :  10.1016/j.bmcl.2012.06.104

来源: Elsevier

【 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.

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