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

Alastair D. Reith, Paul Bamborough, Karamjit Jandu, Daniele Andreotti, Lucy Mensah, Pamela Dossang, Hwan Geun Choi, Xianming Deng, Jinwei Zhang, Dario R. Alessi, Nathanael S. Gray

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    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 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 100 mg/kg.
    Original languageEnglish
    Pages (from-to)5625-5629
    Number of pages5
    JournalBioorganic & Medicinal Chemistry Letters
    Volume22
    Issue number17
    DOIs
    Publication statusPublished - 2012

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    Reith, A. D., Bamborough, P., Jandu, K., Andreotti, D., Mensah, L., Dossang, P., Choi, H. G., Deng, X., Zhang, J., Alessi, D. R., & Gray, N. S. (2012). GSK2578215A: a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor. Bioorganic & Medicinal Chemistry Letters, 22(17), 5625-5629. https://doi.org/10.1016/j.bmcl.2012.06.104