Wadkins Randy M, Hyatt Janice L, Wei Xin, Yoon Kyoung Jin P, Wierdl Monika, Edwards Carol C, Morton Christopher L, Obenauer John C, Damodaran Komath, Beroza Paul, Danks Mary K, Potter Philip M
Department of Chemistry and Biochemistry, University of Mississippi, University, Mississippi 38677, USA.
J Med Chem. 2005 Apr 21;48(8):2906-15. doi: 10.1021/jm049011j.
Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2) > 0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.
羧酸酯酶（CE）是负责代谢外源性物质的普遍存在的酶。由于不同类别的酯酶之间存在结构和氨基酸同源性，已证明鉴定这些蛋白质的选择性抑制剂存在问题。使用Telik的靶标相关亲和力分析（TRAP）技术，我们鉴定出了一类基于联苯甲酰（1,2 - 二苯基乙烷 - 1,2 - 二酮）的化合物，它们是有效的CE抑制剂，其抑制常数（K(i)）值在低纳摩尔范围内。联苯甲酰及其30种类似物表现出对CE的选择性抑制，对人乙酰胆碱酯酶或丁酰胆碱酯酶没有抑制活性。对结构相关化合物的分析表明，乙烷 - 1,2 - 二酮部分对于酶抑制至关重要，并且效力取决于苯环的存在及其取代情况。对这些联苯甲酰类似物针对三种不同哺乳动物CE的三维定量构效关系（3D - QSAR）分析表明，观察到的与预测的K(i)之间具有良好的相关性（r(2) > 0.91），交叉验证系数（q(2)）为0.9。总体而言，这些结果表明可以设计出具有临床应用潜力的CE选择性抑制剂。
