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5-Substituted-N-pyridazinylbenzamides as potent and selective LRRK2 inhibitors: Improved brain unbound fraction enables efficacy |
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| Authors: | Xiao Ding Luigi Piero Stasi Xuedong Dai Kai Long Cheng Peng Baowei Zhao Hailong Wang Changhui Sun Huan Hu Zehong Wan Karamjit S. Jandu Oliver J. Philps Yan Chen Lizhen Wang Qian Liu Colin Edge Yi Li Kelly Dong 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. Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, UK;3. Platform Technology Sciences, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China;4. Platform Technology Sciences, GSK Pharmaceuticals R&D, Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts UK |
| Abstract: | We describe the discovery and optimization of 5-substituted-N-pyridazinylbenzamide derivatives as potent and selective LRRK2 inhibitors. Extensive SAR studies led to the identification of compounds 18 and 23, which demonstrated good in vitro pharmacokinetic profile and excellent selectivity over 140 other kinases. Both compounds demonstrated high unbound fractions in both blood and brain. Compound 18 proved to be brain penetrant, and the high unbound fraction of compound 18 in brain enabled its in vivo efficacy in CNS, wherein a significant inhibition of LRRK2 Ser935 phosphorylation was observed in rat brain following intravenous infusion at 5?mg/kg/h. |
| Keywords: | CNS penetration LRRK2 Parkinson’s disease PFI Unbound fraction |
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