Brain Penetrant LRRK2 Inhibitor

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• 作者：Hwan Geun Choi ; Jinwei Zhang ; Xianming Deng ; John M. Hatcher ; Matthew P. Patricelli ; Zheng Zhao ; Dario R. Alessi ; Nathanael S. Gray
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：3
• 期：8
• 页码：658-662
• 全文大小：335K
• 年卷期：v.3,no.8(August 9, 2012)
• ISSN：1948-5875

文摘

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 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鈥?.3 渭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.

Keywords:

g/action/doSearch?action=search&searchText=LRRK2&qsSearchArea=searchText">LRRK2; g/action/doSearch?action=search&searchText=blood%E2%88%92brain+barrier&qsSearchArea=searchText">blood鈭抌rain barrier; g/action/doSearch?action=search&searchText=brain+penetrant+inhibitor&qsSearchArea=searchText">brain penetrant inhibitor; g/action/doSearch?action=search&searchText=2%2C4%5C-diaminopyrimidine&qsSearchArea=searchText">2,4-diaminopyrimidine