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

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.