Brain Penetrant LRRK2 Inhibitor
ACS Medicinal Chemistry Letters2012Vol. 3(8), pp. 658–662
Citations Over TimeTop 10% of 2012 papers
Hwan Geun Choi, Jinwei Zhang, Xianming Deng, John M. Hatcher, Matthew P. Patricelli, Zheng Zhao, Dario R. Alessi, Nathanael S. Gray
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-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 µM 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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