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.
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02115, United States ; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
authors.forename: John M
authors.initials: JM
authors.lastname: Hatcher
authors.affiliation: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Jinwei
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02115, United States.
authors.forename: Hwan Geun
authors.initials: HG
authors.lastname: Choi
authors.affiliation: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Genta
authors.initials: G
authors.lastname: Ito
authors.affiliation: MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
authors.forename: Dario R
authors.initials: DR
authors.lastname: Alessi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02115, United States ; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School , 360 Longwood Avenue, Longwood Center LC-2209, Boston, Massachusetts 02115, United States.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
keywords: LRRK2; Parkinson’s disease; leucine-rich repeat kinase 2; pharmacokinetics