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

作者：Hatcher John M; Zhang Jinwei; Choi Hwan Geun; Ito Genta; Alessi Dario R^*; Gray Nathanael S

来源：ACS Medicinal Chemistry Letters, 2015, 6(5): 584-589.

DOI：10.1021/acsmedchemlett.5b00064

• LRRK2
• leucine-rich repeat kinase 2
• Parkinson's disease
• pharmacokinetics

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.

• 出版日期2015-5