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Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor.

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 ?M 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.

SUBMITTER: Hatcher JM

PROVIDER: S-EPMC4434483 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor.

Hatcher John M JM Zhang Jinwei J Choi Hwan Geun HG Ito Genta G Alessi Dario R DR Gray Nathanael S NS

ACS medicinal chemistry letters 20150407 5

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 cel ...[more]

PMID: 26005538

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