Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor

John M. Hatcher, Jinwei Zhang, Hwan Geun Choi, Genta Ito, Dario R. Alessi (Lead / Corresponding author), Nathanael S. Gray (Lead / Corresponding author)

    Research output: Contribution to journalArticlepeer-review

    28 Citations (Scopus)

    Abstract

    Activating mutations in leucine-rich repeat kinase 2 (LRRK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here we report a 2-anilino-4-methylamino-5-chloropyrrolopyrimidine, JH-II-127 (18), as a potent and selective inhibitor of both wild-type and G2019S mutant LRRK2. Compound 18 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 μM in a variety of cell types and is capable of inhibiting Ser935 phosphorylation in mouse brain following oral delivery of doses as low as 30 mg/kg.

    Original languageEnglish
    Pages (from-to)584-589
    Number of pages6
    JournalACS Medicinal Chemistry Letters
    Volume6
    Issue number5
    DOIs
    Publication statusPublished - 14 May 2015

    Keywords

    • Leucine-rich repeat kinase 2
    • LRRK2
    • Parkinson's disease
    • Pharmacokinetics

    Fingerprint

    Dive into the research topics of 'Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor'. Together they form a unique fingerprint.

    Cite this