Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors

被引：14

作者：

Ding, Xiao ^{[1
]}

Stasi, Luigi Piero ^{[1
]}

Ho, Ming-Hsun ^{[2
]}

Zhao, Baowei ^{[1
]}

Wang, Hailong ^{[1
]}

Long, Kai ^{[1
]}

Xu, Qiongfeng ^{[1
]}

Sang, Yingxia ^{[1
]}

Sun, Changhui ^{[1
]}

Hu, Huan ^{[1
]}

Yu, Haihua ^{[1
]}

Wan, Zehong ^{[1
]}

Wang, Lizhen ^{[1
]}

Edge, Colin ^{[3
]}

Liu, Qian ^{[2
]}

Li, Yi ^{[2
]}

Dong, Kelly ^{[2
]}

Guan, Xiaoming ^{[1
]}

Tattersall, F. David ^{[1
]}

Reith, Alastair D. ^{[4
]}

Ren, Feng ^{[1
]}

机构：

[1] GSK Pharmaceut R&D, Neurodegenerat DPU, Neurosci Therapeut Area Unit, 898 Halei Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China

[2] GSK Pharmaceut R&D, Platform Technol Sci, 898 Halei Rd,Zhangjiang Hitech Pk, Shanghai 201203, Peoples R China

[3] GSK Pharmaceut R&D, Med Res Ctr, Platform Technol Sci, Gunnels Wood Rd, Stevenage, Herts, England

[4] GSK Pharmaceut R&D, Neurosci Therapeut Area Unit, Med Res Ctr, Neurodegenerat DPU, Gunnels Wood Rd, Stevenage, Herts, England

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2018年 / 28卷 / 09期

关键词：

Pyrrolo[2,3-d]pyrimidine; LRRK2; Parkinson's disease; Kinase selectivity; CNS penetration; KINASE; 2; LRRK2; BRAIN PENETRANT; HIGHLY POTENT;

D O I：

10.1016/j.bmcl.2018.03.045

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Inhibition of LRRK2 kinase activity with small molecules has emerged as a potential novel therapeutic treatment for Parkinson's disease. Herein we disclose the discovery of a 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amine series as potent LRRK2 inhibitors identified through a kinase-focused set screening. Optimization of the physicochemical properties and kinase selectivity led to the discovery of compound 7, which exhibited potent in vitro inhibition of LRRK2 kinase activity, good physicochemical properties and kinase selectivity across the kinome. Moreover, compound 7 was able to penetrate into the CNS, and in vivo pharmacology studies revealed significant inhibition of Ser935 phosphorylation in the brain of both rats (30 and 100 mg/kg) and mice (45 mg/kg) following oral administration. (C) 2018 Published by Elsevier Ltd.

引用

页码：1615 / 1620

页数：6

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