Discovery of thiazole salt AChE inhibitors and development of thiamine disulfide prodrugs targeting the central nervous system

The selective AChE inhibitor donepezil has been approved by the FDA as a first-line drug for the treatment of mild to moderate AD. However, many peripheral side effects were observed in patients taking donepezil. Our main objective here is to provide insight into the opportunities and challenges associated with development of AChE inhibitors with high brain exposure and low peripheral side effects. In this study, we have for the first time revealed a series of novel thiazole salt AChE inhibitors, which exhibit a nanomolar inhibitory effect on human AChE. We further developed thiamine disulfide prodrugs based on optimized thiazole salt AChE inhibitors, which are reduced in the brain to form thiazole salt AChE inhibitors. In vivo experiments have confirmed that the representative prodrug Tap4 (i.p., 10 mg/kg) can be converted into the thiazole salt AChE inhibitor Tat2 and shows high brain exposure, reaching 500 ng/g. Further, the inhibitory effect of the prodrug Tap4 on AChE is obviously stronger in the brain than that on intestinal AChE of ICR mice. Our study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.