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

doi:10.1021/acs.jmedchem.0c01863

	Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate
	Zhou, Yu 3,6; Fu, Yan 1; Yin, Wanchao 1; Li, Jian 5,6; Wang, Wei 1; Bai, Fang 2,4; Xu, Shengtao 6; Gong, Qi 1; Peng, Tao 6; Hong, Yu 6
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2021-02-25
卷号	64 期号:4 页码:1844-1855
ISSN号	0022-2623
DOI	10.1021/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
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/295570]
专题	中国科学院上海药物研究所
通讯作者	Zhang, Haiyan; Jiang, Hualiang; Liu, Hong
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 2.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 3.Univ Chinese Acad Sci, Sch Pharm, Beijing 100049, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 6.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, 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.