一系列人中性粒细胞弹性蛋白酶的基于机制抑制剂中结构对抑制活性的影响。
Effects of structure on inhibitory activity in a series of mechanism-based inhibitors of human neutrophil elastase.
机构信息
Department of Chemistry, Wichita State University, Wichita, KS 67260, United States.
出版信息
Bioorg Med Chem. 2010 Sep 15;18(18):6646-50. doi: 10.1016/j.bmc.2010.07.071. Epub 2010 Aug 5.
Abstract
A structurally-diverse series of carboxylate derivatives based on the 1,2,5-thiadiazolidin-one 1,1 dioxide scaffold were synthesized and used to probe the S' subsites of human neutrophil elastase (HNE) and neutrophil proteinase 3 (Pr 3). Several compounds are potent inhibitors of HNE but devoid of inhibitory activity toward Pr 3, suggesting that the S' subsites of HNE exhibit significant plasticity and can, unlike Pr 3, tolerate various large hydrophobic groups. The results provide a promising framework for the design of highly selective inhibitors of the two enzymes.
摘要
合成了一系列基于 1,2,5-噻二唑烷-1,1-二氧化物骨架的结构多样的羧酸衍生物，并将其用于探测人中性粒细胞弹性蛋白酶（HNE）和中性粒细胞蛋白酶 3（Pr3）的 S'亚基。几种化合物是 HNE 的有效抑制剂，但对 Pr3 没有抑制活性，这表明 HNE 的 S'亚基具有显著的可塑性，与 Pr3 不同，它可以容纳各种大的疏水基团。这些结果为设计这两种酶的高选择性抑制剂提供了有希望的框架。
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