Sugimoto H, Yamanishi Y, Iimura Y, Kawakami Y
Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki, 300-2635, Japan.
Curr Med Chem. 2000 Mar;7(3):303-39. doi: 10.2174/0929867003375191.
A wide range of evidence shows that acetylcholinesterase (AChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The successful development of these compounds was based on a well-accepted theory that the decline in cognitive and mental functions associated with AD is related to the loss of cortical cholinergic neurotransmission. The earliest known AChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of Alzheimer's 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 inhibitor that would overcome the disadvantages of these two compounds. Donepezil hydrochloride inaugurates a new class of AChE inhibitors with longer and more selective action with manageable adverse effects. Currently, there are about 19 new Alzheimer's drugs in various phases of clinical development.
大量证据表明，乙酰胆碱酯酶（AChE）抑制剂可干扰阿尔茨海默病（AD）的进展。这些化合物的成功研发基于一个广为接受的理论，即与AD相关的认知和心理功能衰退与皮质胆碱能神经传递的丧失有关。最早已知的AChE抑制剂，即毒扁豆碱和他克林，在阿尔茨海默病患者的认知功能方面显示出适度改善。然而，临床研究表明，毒扁豆碱的口服活性、脑渗透性和药代动力学参数较差，而他克林具有肝毒性。随后的研究集中在寻找一种新型的乙酰胆碱酯酶抑制剂，以克服这两种化合物的缺点。盐酸多奈哌齐开创了一类新型的AChE抑制剂，其作用时间更长、更具选择性，且不良反应可控。目前，约有19种治疗阿尔茨海默病的新药正处于临床开发的不同阶段。
