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Brain penetrant LRRK2 inhibitor

Brain penetrant LRRK2 inhibitor

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Authors

  • Hwan Geun Choi
  • Jinwei Zhang
  • Xianming Deng
  • John M. Hatcher
  • Matthew P. Patricelli
  • Zheng Zhao
  • Dario R. Alessi
  • Nathanael S. Gray

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Info

Original languageEnglish
Pages658-662
Number of pages5
JournalACS Medicinal Chemistry Letters
Journal publication dateAug 2012
Journal number8
Volume3
DOIs
StatePublished

Abstract

Activating mutations in leucine-rich repeat kinase 2 (LARK2) are present in a subset of Parkinson's disease (PD) patients and may represent an attractive therapeutic target. Here, we report that a 2-anilino-4-methylamino-5-chloropyrimidine, HG-10-102-01 (4), is a potent and selective inhibitor of wild-type LRRK2 and the G2019S mutant. Compound 4 substantially inhibits Ser910 and Ser935 phosphorylation of both wild-type LRRK2 and G2019S mutant at a concentration of 0.1-0.3 mu M in cells and is the first compound reported to be capable of inhibiting Ser910 and Ser935 phosphorylation in mouse brain following intraperitoneal delivery of doses as low as 50 mg/kg.

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