Discovery and development of donepezil hydrochloride for the treatment of Alzheimer's disease

The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the los s of neurons in the basal forebrain. The most widely studied acetylcholines terase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmi ne has very short duration, and tacrine has liability to hepatotoxicity. Th ese are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacri ne. Through a random screening, we incidentally found an N-benzylpiperazine der ivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a drama tic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-am ide derivative showed enhanced inhibitory activity. On the basis of these r esults, an indanone derivative was designed. Among these indanone derivativ es, 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 cogni tive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).