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

Abstract	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.
Authors	Yu Zhou, Yan Fu, Wanchao Yin, Jian Li, Wei Wang, Fang Bai, Shengtao Xu, Qi Gong, Tao Peng, Yu Hong, Dong Zhang, Dan Zhang, Qiufeng Liu, Yechun Xu, H Eric Xu, Haiyan Zhang, Hualiang Jiang, Hong Liu
Journal	Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 4 Pg. 1844-1855 (02 25 2021) ISSN: 1520-4804 [Electronic] United States
PMID	33570950 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cholinesterase Inhibitors Indans Nootropic Agents Piperidines Scopolamine Acetylcholinesterase
Topics	Acetylcholinesterase (metabolism) Alzheimer Disease (chemically induced, drug therapy) Animals Cholinesterase Inhibitors (chemical synthesis, metabolism, therapeutic use) Crystallography, X-Ray Dogs Drug Design Female Humans Indans (chemical synthesis, metabolism, therapeutic use) Kinetics Male Mice, Inbred ICR Molecular Structure Nootropic Agents (chemical synthesis, metabolism, therapeutic use) Piperidines (chemical synthesis, metabolism, therapeutic use) Protein Binding Rats, Sprague-Dawley Scopolamine Structure-Activity Relationship Mice Rats

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!