Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor
Discovery of a Pyrrolopyrimidine (JH-II-127), a Highly Potent, Selective, and Brain Penetrant LRRK2 Inhibitor
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DOI：
10.1021/acsmedchemlett.5b00064
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发表时间：
2015-05-01
影响因子：
4.2
通讯作者：
Gray, Nathanael S.
中科院分区：
文献类型：
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作者：
Hatcher, John M.;Zhang, Jinwei;Gray, Nathanael S.
富含亮氨酸的重复蛋白激酶2(LRRK2)的激活突变存在于帕金森病(PD)患者的一部分中，可能代表着一个有吸引力的治疗靶点。在此，我们报道了一株2-anilino-4-methylamino-5-chloropyrrolopyrimidine，JH-II-127(18)，作为野生型和G2019S突变体LRRK2的有效和选择性抑制剂。化合物18在0.1-0.3µM的浓度下，在多种细胞类型中显著抑制野生型LRRK2和G2019S突变体的Ser910和Ser935的磷酸化，并能够在低至30 mg/kg的剂量下抑制小鼠脑内Ser935的磷酸化。
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.