发现5-取代-N-芳基苯甲酰胺衍生物作为强效、选择性且口服生物可利用的LRRK2抑制剂。
Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors.
作者信息
Ding Xiao, Dai Xuedong, Long Kai, Peng Cheng, Andreotti Daniele, Bamborough Paul, Eatherton Andrew J, Edge Colin, Jandu Karamjit S, Nichols Paula L, Philps Oliver J, Stasi Luigi Piero, Wan Zehong, Xiang Jia-Ning, Dong Kelly, Dossang Pamela, Ho Ming-Hsun, Li Yi, Mensah Lucy, Guan Xiaoming, Reith Alastair D, Ren Feng
机构信息
Neurodegeneration DPU, Neurosciences Therapeutic Area Unit, GSK Pharmaceuticals R&D, 898 Halei Road, Zhangjiang Hi-Tech Park, Pudong, Shanghai 201203, PR China.
Neurosciences CEDD, GSK Pharmaceuticals R&D, Verona, Italy.
出版信息
Bioorg Med Chem Lett. 2017 Sep 1;27(17):4034-4038. doi: 10.1016/j.bmcl.2017.07.052. Epub 2017 Jul 21.
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.
富含亮氨酸重复激酶2（LRRK2）已被认为是帕金森病的一个潜在治疗靶点。在此我们报告发现5-取代-N-芳基苯甲酰胺衍生物作为新型LRRK2抑制剂。广泛的构效关系研究导致发现了化合物8e，其表现出强效的LRRK2抑制活性、在激酶组中的高选择性、良好的脑内暴露以及高口服生物利用度。
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