Effects of structure on inhibitory activity in a series of mechanism-based inhibitors of human neutrophil elastase

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• 作者：Dengfeng Dou ; Guijia He ; Rongze Kuang ; Qingfong Fu ; Radhika Venkataraman ; William C. Groutas
• 关键词：Neutrophil elastase ; Inhibitors
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2010
• 出版时间：15 September 2010
• 年：2010
• 卷：18
• 期：18
• 页码：6646-6650
• 全文大小：670 K

文摘

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.