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

    Research output: Contribution to journalArticlepeer-review

    133 Citations (Scopus)

    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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