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Discovery of 5-substituent-N-arylbenzamide derivatives as potent,selective and orally bioavailable LRRK2 inhibitors |
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| Authors: | Xiao Ding Xuedong Dai Kai Long Cheng Peng Daniele Andreotti Paul Bamborough Andrew J. Eatherton Colin Edge Karamjit S. Jandu Paula L. Nichols Oliver J. Philps Luigi Piero Stasi Zehong Wan Jia-Ning Xiang Kelly Dong Pamela Dossang Ming-Hsun Ho Yi Li Feng Ren |
| Affiliation: | 1. Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China;2. Neurosciences CEDD, GSK Pharmaceuticals R&D, Verona, Italy;3. Platform Technology Sciences, GSK Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, UK;4. Neurosciences CEDD, GSK Pharmaceuticals R&D, New Frontiers Science Park, Harlow, Essex, UK;5. Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, UK;6. Platform Technology Sciences, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China |
| 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: | Parkinson’s disease LRRK2 inhibitor Arylbenzamide CNS penetration Kinase selectivity |
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