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. 2017 Sep 1;27(17):4034-4038.
doi: 10.1016/j.bmcl.2017.07.052. Epub 2017 Jul 21.

Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors

Xiao Ding  1 , Xuedong Dai  1 , Kai Long  1 , Cheng Peng  1 , Daniele Andreotti  2 , Paul Bamborough  3 , Andrew J Eatherton  4 , Colin Edge  3 , Karamjit S Jandu  5 , Paula L Nichols  4 , Oliver J Philps  5 , Luigi Piero Stasi  1 , Zehong Wan  1 , Jia-Ning Xiang  1 , Kelly Dong  6 , Pamela Dossang  3 , Ming-Hsun Ho  6 , Yi Li  6 , Lucy Mensah  3 , Xiaoming Guan  1 , Alastair D Reith  7 , Feng Ren  8
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Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors

Xiao Ding et al. Bioorg Med Chem Lett. .

Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.

Keywords: Arylbenzamide; CNS penetration; Kinase selectivity; LRRK2 inhibitor; Parkinson’s disease.

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