SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF ACETYLCHOLINESTERASE INHIBITORS - 1-BENZYL-4-[(5,6-DIMETHOXY-1-OXOINDAN-2-YL)METHYL]PIPERIDINE HYDROCHLORIDE AND RELATED-COMPOUNDS

被引:308
作者
SUGIMOTO, H [1 ]
IIMURA, Y [1 ]
YAMANISHI, Y [1 ]
YAMATSU, K [1 ]
机构
[1] EISAI & CO LTD,TSUKUBA RES LABS,TSUKUBA,IBARAKI 30026,JAPAN
关键词
D O I
10.1021/jm00024a009
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Following the discovery of a new series of anti-acetylcholinesterase (anti-AChE) inhibitors such as 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine (1), we reported that its rigid analogue, 1-benzyl-4-(2-isoindolin-2-ylethyl)piperidine (5), had more potent activity. We have extended the structure-activity relationship (SAR) study for the rigid analogue and found that the 2-isoindoline moiety in compound 5 can be replaced with a indanone moiety (8) without a major loss in potency. Among the indanone derivatives, 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2yl)methyl]piperidine (13e) (E2020) (IC50 = 5.7 nM) was found to be one of the most potent anti-AChE inhibitors. Compound 13e showed a selective affinity 1250 times greater for AChE than for butyrylcholinesterase. In vivo studies demonstrated that 13e has a longer duration of action than physostigmine at a dose of 5 mg/kg (po) and produced a marked and significant increase in acetylcholine content in rat cerebral cortex. We report the synthesis, SAR, and a proposed hypothetical binding site of 13e (E2020).
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页码:4821 / 4829
页数:9
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