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Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate

文献类型：期刊论文

作者Zhou, Yu2,3; Fu, Yan4; Yin, Wanchao4; Li, Jian2,5; Wang, Wei4; Bai, Fang1,6; Xu, Shengtao2; Gong, Qi4; Peng, Tao2; Hong, Yu2
刊名JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021-02-25
卷号64期号:4页码:1844-1855
ISSN号0022-2623
DOI10.1021/acs.jmedchem.0c01863
通讯作者Zhang, Haiyan(hzhang@simm.ac.cn) ; Jiang, Hualiang(hijiang@simm.ac.cn) ; Liu, Hong(hliu@simm.ac.cn)
英文摘要The acetylcholinesterase (AChE) inhibitors remain key therapeutic drugs for the treatment of Alzheimer's disease (AD). However, the low-safety window limits their maximum therapeutic benefits. Here, a novel kinetics-driven drug design strategy was employed to discover new-generation AChE inhibitors that possess a longer drug-target residence time and exhibit a larger safety window. After detailed investigations, compound 12 was identified as a highly potent, highly selective, orally bioavailable, and brain preferentially distributed AChE inhibitor. Moreover, it significantly ameliorated cognitive impairments in different mouse models with a lower effective dose than donepezil. The X-ray structure of the cocrystal complex provided a precise binding mode between 12 and AChE. Besides, the data from the phase I trials demonstrated that 12 had good safety, tolerance, and pharmacokinetic profiles at all preset doses in healthy volunteers, providing a solid basis for its further investigation in phase II trials for the treatment of AD.
资助项目National Natural Science Foundation of China[81102307] ; National Natural Science Foundation of China[21632008] ; National S&T Major Projects[2015ZX09103003] ; National S&T Major Projects[2018ZX09711002] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040207] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040106] ; Youth Innovation Promotion Association CAS ; Jiangsu Kanion Pharmaceutical Co. Ltd.
WOS研究方向Pharmacology & Pharmacy
语种英语
出版者AMER CHEMICAL SOC
WOS记录号WOS:000624369300005
源URL[http://119.78.100.183/handle/2S10ELR8/295570]  
专题新药研究国家重点实验室
通讯作者Zhang, Haiyan; Jiang, Hualiang; Liu, Hong
作者单位1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China
3.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China
4.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China
5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China
6.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
推荐引用方式
GB/T 7714		 Zhou, Yu,Fu, Yan,Yin, Wanchao,et al. Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(4):1844-1855.
APA Zhou, Yu.,Fu, Yan.,Yin, Wanchao.,Li, Jian.,Wang, Wei.,...&Liu, Hong.(2021).Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate.JOURNAL OF MEDICINAL CHEMISTRY,64(4),1844-1855.
MLA Zhou, Yu,et al."Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate".JOURNAL OF MEDICINAL CHEMISTRY 64.4(2021):1844-1855.

入库方式： OAI收割

来源：上海药物研究所

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