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

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

  • ACS Med Chem Lett. 2015 Apr 7;6(5):584-9. doi: 10.1021/acsmedchemlett.5b00064.
John M Hatcher 1,  Jinwei Zhang 2,  Hwan Geun Choi 3,  Genta Ito 2,  Dario R Alessi 2,  Nathanael S Gray 1
Affiliations

Affiliations

  • 1 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.
  • 2 MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee , Dow Street, Dundee DD1 5EH, Scotland, United Kingdom.
  • 3 Department of Cancer Biology, Dana-Farber Cancer Institute , Boston, Massachusetts 02115, United States.
PMID: 26005538 DOI: 10.1021/acsmedchemlett.5b00064
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

LRRK2; Parkinson’s disease; leucine-rich repeat kinase 2; pharmacokinetics.

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