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; Nathanael S. Gray

doi:10.1021/acsmedchemlett.5b00064

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 journal › Article › peer-review

48 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 language	English
Pages (from-to)	584-589
Number of pages	6
Journal	ACS Medicinal Chemistry Letters
Volume	6
Issue number	5
DOIs	https://doi.org/10.1021/acsmedchemlett.5b00064
Publication status	Published - 14 May 2015

Keywords

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

ASJC Scopus subject areas

Organic Chemistry
Drug Discovery
Biochemistry

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10.1021/acsmedchemlett.5b00064

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title = "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 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.",

keywords = "Leucine-rich repeat kinase 2, LRRK2, Parkinson's disease, Pharmacokinetics",

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AU - Hatcher, John M.

AU - Zhang, Jinwei

AU - Choi, Hwan Geun

AU - Ito, Genta

AU - Alessi, Dario R.

AU - Gray, Nathanael S.

PY - 2015/5/14

Y1 - 2015/5/14

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AB - 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.

KW - Leucine-rich repeat kinase 2

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KW - Parkinson's disease

KW - Pharmacokinetics

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

Abstract

Keywords

ASJC Scopus subject areas

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Role of fbx07 in Parkinson's Disease (Studentship)

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

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Role of fbx07 in Parkinson's Disease (Studentship)

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