Sugimoto H, Yamanishi Y, Ogura H, Iimura Y, Yamatsu K
Tsukuba Research Laboratories for Drug Discovery, Eisai Co., Ltd., Ibaraki, Japan.
Yakugaku Zasshi. 1999 Feb;119(2):101-13. doi: 10.1248/yakushi1947.119.2_101.
The most consistent change of neurotransmitter in the brain of Alzheimer's patients is the dramatic decrease of cholinergic innervation due to the loss of neurons in the basal forebrain. The most widely studied acetylcholinesterase inhibitors (AChEIs) have been physostigmine and tacrine. Physostigmine has very short duration, and tacrine has liability to hepatotoxicity. These are the defects of the inhibitors. Our objective was to find a new type of AChEIs that would overcome the disadvantages of physostigmine and tacrine. Through a random screening, we incidentally found an N-benzylpiperazine derivative which showed positive cholinergic behavior in rats. We replaced the N-benzylpiperazine moiety with N-benzylpiperidine moiety and found a dramatic increase in anti-AChE activity. Even after the replacement of an amide group with a ketone group the activity was held. Furthermore, the cyclic-amide derivative showed enhanced inhibitory activity. On the basis of these results, an indanone derivative was designed. Among these indanone derivatives, 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 cognitive sub.) and CIBIC Plus (Clinician's Interview-Based Impression of Change plus).
阿尔茨海默病患者大脑中最一致的神经递质变化是由于基底前脑神经元丢失导致胆碱能神经支配显著减少。研究最广泛的乙酰胆碱酯酶抑制剂（AChEIs）是毒扁豆碱和他克林。毒扁豆碱作用持续时间非常短，他克林有肝毒性倾向。这些都是抑制剂的缺陷。我们的目标是找到一种新型的AChEIs，以克服毒扁豆碱和他克林的缺点。通过随机筛选，我们偶然发现一种N-苄基哌嗪衍生物在大鼠中表现出阳性胆碱能行为。我们用N-苄基哌啶部分取代N-苄基哌嗪部分，发现抗乙酰胆碱酯酶活性显著增加。即使将酰胺基团替换为酮基团后，活性依然保持。此外，环酰胺衍生物显示出增强的抑制活性。基于这些结果，设计了茚满酮衍生物。在这些茚满酮衍生物中，盐酸多奈哌齐（E2020），商品名安理申，被发现是最平衡的化合物。盐酸多奈哌齐的临床研究表明，其对ADAS-cog（阿尔茨海默病评估量表认知部分）和CIBIC Plus（基于临床医生访谈的变化印象加）有统计学上的显著效果。
