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

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....

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Bibliographic Details
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
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Summary: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.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2007.10.041