The new approach in development of anti-Alzheimer's disease drugs via the cholinergic hypothesis.
A wide range of evidences show 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 (SAR) study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Recently, acetylcholinesterase inhibitors (AChEIs) have been studied for other mechanisms of action, such as neuroprotective action and lowering of beta-amyloid (beta-amyloid). Donepezil also reduced beta-amyloid plaque in in vitro. The amyloid hypothesis is believed to be the most promising approach in the development of anti-AD drugs. We speculate the mechanism of lowering beta-amyloid by donepezil implicate alpha-secretase (alpha-secretase) enhancer.
Sugimoto
Hachiro
H
Department of Neuroscience for Drug Discovery, Graduate School of Pharmaceutical Science, Kyoto University, Yoshida-Shimodachi-cho, Sakyo-ku, Kyoto, Japan. hsugimot@pharm.kyoto-u.ac.jp
D000544:Alzheimer Disease / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy; D000077265:Donepezil; D015195:Drug Design; D006801:Humans; D007189:Indans / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D002800:Cholinesterase Inhibitors; D007189:Indans; D018696:Neuroprotective Agents; D010880:Piperidines; D000077265:Donepezil