Kinetics-Driven Drug Design Strategy for Next-Generation Acetylcholinesterase Inhibitors to Clinical Candidate
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, H. Eric Xu, Haiyan Zhang, Hualiang Jiang, Hong Liu
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.