多奈哌齐
乙酰胆碱酯酶
化学
药理学
药代动力学
治疗窗口
药品
共晶
乙酰胆碱酯酶抑制剂
阿切
酶
疾病
生物化学
内科学
医学
痴呆
氢键
有机化学
分子
作者
Yu Zhou,Yan Fu,Wanchao Yin,Jian Li,Wei Wang,Fang Bai,Shengtao Xu,Qi Gong,Tao Peng,Hong Yu,Dong Zhang,Dan Zhang,Qiufeng Liu,Yechun Xu,Haiyan Zhang,Hualiang Jiang,Hong Liu
标识
DOI:10.1021/acs.jmedchem.0c01863
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.
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