Research and Development of Donepezil Hydrochloride, a New Type of Acetylcholinesterase Inhibitor

The Japanese Journal of Pharmacology

Youichi Iimura¹  Yoshiharu Yamanishi²  Hachiro Sugimoto¹  Yasuo Arai³  Hiroo Ogura¹ 

[1]Tsukuba Research Laboratories, Eisai Co., Ltd.

[2]Eisai London Research Laboratories Ltd.

[3]Clinical Research Center of Japan, Eisai Co., Ltd.

关键词: Donepezil;    Alzheimer’s disease;    Acetylcholinesterase inhibitor;    Structure-activity relationship;    Placebo controlled study in Japan;   

DOI  :  10.1254/jjp.89.7

学科分类：药理学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(62)Cited-By(74)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.

【 授权许可】

Unknown