Inactivation of human neutrophil elastase by 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamides

• Published in: Bioorganic & medicinal chemistry 2008-01, Vol.16 (2), p.692-698
• Main Authors: Li, Yi, Yang, Qingliang, Dou, Dengfeng, Alliston, Kevin R., Groutas, William C.
• Format: Article
• Language: English
• Subjects: Algorithms; Animals; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cathepsin G; Cathepsins - antagonists & inhibitors; Combinatorial Chemistry Techniques; Drug Design; Humans; Inhibitors; Leukocyte Elastase - antagonists & inhibitors; Medical sciences; Molecular Structure; Myeloblastin - antagonists & inhibitors; Pharmacology. Drug treatments; Respiratory system; Serine; Serine Endopeptidases; Serine Proteinase Inhibitors - chemical synthesis; Serine Proteinase Inhibitors - chemistry; Serine Proteinase Inhibitors - pharmacology; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thiadiazoles - chemical synthesis; Thiadiazoles - chemistry; Thiadiazoles - pharmacology
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2007.10.041

A series of 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamides (I) were found to be potent and selective inhibitors of human neutrophil elastase. The interaction of a series of 1,2,5-thiadiazolidin-3-one 1,1 dioxide-based sulfonamides with neutrophil-derived serine proteases was investigated. The nature of the amino acid component, believed to be oriented toward the S′ subsites, had a profound effect on enzyme selectivity. This series of compounds were found to be potent, time-dependent inhibitors of human neutrophil elastase (HNE) and were devoid of any inhibitory activity toward neutrophil proteinase 3 (PR 3) and cathepsin G (Cat G). The results of these studies demonstrate that exploitation of differences in the S′ subsites of HNE and PR 3 can lead to highly selective inhibitors of HNE.