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

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Issue Date
2010-09-15
Authors
Dou, Dengfeng
He, Guijia
Kuang, Rongze
Fu, Qingfong
Venkataraman, Radhika
Groutas, William C.
Advisor
Citation

Bioorganic & medicinal chemistry. 2010 Sep 15; 18(18): 6646-50.

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.

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