Brain penetrant LRRK2 inhibitor

TY - JOUR

T1 - Brain penetrant LRRK2 inhibitor

A1 - Choi,Hwan Geun

A1 - Zhang,Jinwei

A1 - Deng,Xianming

A1 - Hatcher,John M.

A1 - Patricelli,Matthew P.

A1 - Zhao,Zheng

A1 - Alessi,Dario R.

A1 - Gray,Nathanael S.

AU - Choi,Hwan Geun

AU - Zhang,Jinwei

AU - Deng,Xianming

AU - Hatcher,John M.

AU - Patricelli,Matthew P.

AU - Zhao,Zheng

AU - Alessi,Dario R.

AU - Gray,Nathanael S.

PY - 2012/8

Y1 - 2012/8

N2 - <p>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.</p>

AB - <p>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.</p>

U2 - 10.1021/ml300123a

DO - 10.1021/ml300123a

M1 - Article

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

SN - 1948-5875

IS - 8

VL - 3

SP - 658

EP - 662

ER -