Brain Penetrant LRRK2 Inhibitor

被引：110

作者：

Choi, Hwan Geun ^{[2
,3
]}

Zhang, Jinwei ^{[1
]}

Deng, Xianming ^{[2
,3
]}

Hatcher, John M. ^{[2
,3
]}

Patricelli, Matthew P. ^{[4
]}

Zhao, Zheng ^{[5
]}

Alessi, Dario R. ^{[1
]}

Gray, Nathanael S. ^{[2
,3
]}

机构：

[1] Univ Dundee, Coll Life Sci, MRC Prot Phosphorylat Unit, Dundee DD1 5EH, Scotland

[2] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, SGM 628, Boston, MA 02115 USA

[4] ActivX Biosci, La Jolla, CA 92037 USA

[5] Chinese Acad Sci, High Field Magnet Lab, Hefei 230031, Anhui, Peoples R China

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 08期

基金：

英国医学研究理事会;

关键词：

LRRK2; blood-brain barrier; brain penetrant inhibitor; 2,4-diaminopyrimidine; KINASE; 2; LRRK2; PARKINSONS-DISEASE; POTENT; NEURODEGENERATION; SELECTIVITY; TOXICITY; MODELS;

D O I：

10.1021/ml300123a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：658 / 662

页数：5

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