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

被引：49

作者：

Hatcher, John M. ^{[1
,2
]}

Zhang, Jinwei ^{[3
]}

Choi, Hwan Geun ^{[1
]}

Ito, Genta ^{[3
]}

Alessi, Dario R. ^{[3
]}

Gray, Nathanael S. ^{[1
,2
]}

机构：

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

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

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

来源：

ACS MEDICINAL CHEMISTRY LETTERS | 2015年 / 6卷 / 05期

基金：

英国医学研究理事会;

关键词：

LRRK2; leucine-rich repeat kinase 2; Parkinson's disease; pharmacokinetics; KINASE; 2; LRRK2; PARKINSONS-DISEASE;

D O I：

10.1021/acsmedchemlett.5b00064

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 (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 mu M 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.

引用

页码：584 / 589

页数：6

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