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2-苄基氨基甲酸-5-水杨酸盐异山梨醇酯，外周阴离子部位结合的纳摩尔级选择性丁酰胆碱酯酶抑制剂。

Isosorbide-2-benzyl carbamate-5-salicylate, a peripheral anionic site binding subnanomolar selective butyrylcholinesterase inhibitor.

机构信息

School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.

出版信息

J Med Chem. 2010 Feb 11;53(3):1190-9. doi: 10.1021/jm9014845.

DOI:10.1021/jm9014845
PMID:20067290
Abstract

Isosorbide-2-benzyl carbamate-5-benzoate is a highly potent and selective BuChE inhibitor. Meanwhile, isosorbide-2-aspirinate-5-salicylate is a highly effective aspirin prodrug that relies on the salicylate portion to interact productively with human BuChE. By integrating the salicylate group into the carbamate design, we have produced isosorbide-2-benzyl carbamate-5-salicylate, an inhibitor of high potency (150 pM) and selectivity for human BuChE over AChE (666000) and CES2 (23000). Modeling and mutant studies indicate that it achieves its exceptional potency because of an interaction with the polar D70/Y332 cluster in the PAS of BuChE in addition to pseudosubstrate interactions with the active site.

摘要

2-苄基氨基甲酸-5-苯甲酸异山梨酯是一种高效且选择性的丁酰胆碱酯酶抑制剂。同时，2-乙酰水杨酸异山梨酯是一种高效的阿司匹林前药，其依赖于水杨酸部分与人类丁酰胆碱酯酶进行有效相互作用。通过将水杨酸基团整合到氨基甲酸酯设计中，我们生成了 2-苄基氨基甲酸-5-水杨酸酯，它对人丁酰胆碱酯酶具有高抑制活性（150 pM）和选择性（对乙酰胆碱酯酶的选择性为 666000，对羧酸酯酶 2 的选择性为 23000）。建模和突变研究表明，它之所以具有如此出色的活性，是因为它与丁酰胆碱酯酶 PAS 中的极性 D70/Y332 簇相互作用，此外还与活性位点的伪底物相互作用。

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