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Bioorg Med Chem Lett. 2012 Sep 1;22(17):5625-9. doi: 10.1016/j.bmcl.2012.06.104. Epub 2012 Jul 7.

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

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1
External Alliances & Development, R&D China, GlaxoSmithKline Pharmaceuticals R&D, Stevenage, UK. alastair.d.reith@gsk.com

Abstract

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 μM in cells and in mouse spleen and kidney, but not in brain, following intraperitoneal injection of 100mg/kg.

PMID:
22863203
PMCID:
PMC4208292
DOI:
10.1016/j.bmcl.2012.06.104
[Indexed for MEDLINE]
Free PMC Article
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