title: Research and development of donepezil hydrochloride, a new type of acetylcholinesterase inhibitor.
abstract: A wide range of evidence shows that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters, while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Donepezil showed several positive characteristics including the following: 1) It has a novel structure compared to other conventional ChE inhibitors; 2) It shows strong anti-AChE activity and has long lasting efficacy; 3) The inhibitory characteristic of donepezil shows that it is highly selective for AChE as compared to butyrylcholinesterase (BuChE) and showed reversibility; 4) The results of clinical studies on donepezil show a very high significant difference on ADAS cog and CIBIC plus scores of AD patients. Donepezil is currently marketed in 56 countries all over the world.
authors.affiliation: Tsukuba Research Institute Laboratories, Eisai Co, Ltd, Ibaraki, Japan. h-sugimoto@hhc.eisai.co.jp
authors.forename: Hachiro
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Hiroo
authors.initials: H
authors.lastname: Ogura
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Arai
authors.forename: Youichi
authors.initials: Y
authors.lastname: Limura
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Yamanishi
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D000077265:Donepezil; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D000077265:Donepezil