The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, donepazil hydrochloride (E2020), brand name ARICEPT was found to be the most balanced compound. The clinical studies of donepezil hydrochloride demonstrated statistically significant effects on ADAS-cog (Alzheimer's Disease Assessment Scale cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).
