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 journalArticle

    22 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

    Fingerprint

    Leucine
    Brain
    Phosphorylation
    Phosphotransferases
    Parkinson Disease
    Mutation
    pyrrolopyrimidine
    Therapeutics
    compound 18

    Keywords

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

    Cite this

    Hatcher, John M. ; Zhang, Jinwei ; Choi, Hwan Geun ; Ito, Genta ; Alessi, Dario R. ; Gray, Nathanael S. / Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor. In: ACS Medicinal Chemistry Letters. 2015 ; Vol. 6, No. 5. pp. 584-589.
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    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.",
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    Discovery of a pyrrolopyrimidine (JH-II-127), a highly potent, selective, and brain penetrant LRRK2 inhibitor. / Hatcher, John M.; Zhang, Jinwei; Choi, Hwan Geun; Ito, Genta; Alessi, Dario R. (Lead / Corresponding author); Gray, Nathanael S. (Lead / Corresponding author).

    In: ACS Medicinal Chemistry Letters, Vol. 6, No. 5, 14.05.2015, p. 584-589.

    Research output: Contribution to journalArticle

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