1. Discovery of 4-ethoxy-7H-pyrrolo[2,3-d]pyrimidin-2-amines as potent, selective and orally bioavailable LRRK2 inhibitors.
- Author
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Ding, Xiao, Stasi, Luigi Piero, Ho, Ming-Hsun, Zhao, Baowei, Wang, Hailong, Long, Kai, Xu, Qiongfeng, Sang, Yingxia, Sun, Changhui, Hu, Huan, Yu, Haihua, Wan, Zehong, Wang, Lizhen, Edge, Colin, Liu, Qian, Li, Yi, Dong, Kelly, Guan, Xiaoming, Tattersall, F. David, and Reith, Alastair D.
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PYRIMIDINES , *DARDARIN , *ORAL drug administration , *PYRROLES , *DRUG development , *DRUG bioavailability , *THERAPEUTICS - Abstract
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-7 H -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. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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