Carolan Ciaran G, Dillon Gerald P, Gaynor Joanne M, Reidy Sean, Ryder Sheila A, Khan Denise, Marquez Juan F, Gilmer John F
School of Pharmacy and Pharmaceutical Sciences, Trinity College, Dublin 2, Ireland.
J Med Chem. 2008 Oct 23;51(20):6400-9. doi: 10.1021/jm800564y. Epub 2008 Sep 26.
In this study, we report the SAR and characterization of two groups of isosorbide-based cholinesterase inhibitors. The first was based directly on the clinically used nitrate isosorbide mononitrate (ISMN) retention of the 5-nitrate group and introduction of a series of 2-carbamate functionalities. The compounds proved to be potent and selective inhibitors of human plasma butyrylcholinesterase ( huBuChE). In the second group, the nitrate ester was removed and replaced with a variety of alkyl and aryl esters. These generally exhibited nanomolar potency with high selectivity for BuChE over acetylcholinesterase (AChE). The most potent and selective compound was isosorbide-2-benzyl carbamate-5-benzoate with an IC 50 of 4.3 nM for BuChE and >50000 fold selectivity over human erythrocyte AChE. Inhibition with these compounds is time-dependent, competitive, and slowly reversible, indicating active site carbamylation.
在本研究中，我们报告了两组基于异山梨醇的胆碱酯酶抑制剂的构效关系（SAR）及特性。第一组直接基于临床使用的硝酸盐单硝酸异山梨酯（ISMN），保留5-硝酸盐基团并引入一系列2-氨基甲酸酯官能团。这些化合物被证明是人类血浆丁酰胆碱酯酶（huBuChE）的强效和选择性抑制剂。在第二组中，硝酸酯被去除并用各种烷基和芳基酯取代。这些化合物通常表现出纳摩尔级的效力，对丁酰胆碱酯酶（BuChE）的选择性远高于乙酰胆碱酯酶（AChE）。最有效和选择性最强的化合物是异山梨醇-2-苄基氨基甲酸酯-5-苯甲酸酯，对BuChE的IC50为4.3 nM，对人类红细胞AChE的选择性超过50000倍。这些化合物的抑制作用是时间依赖性、竞争性且缓慢可逆的，表明存在活性位点氨甲酰化。
