N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases

The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-06, Vol.22 (12), p.3993-3997
Main Authors: Santana, Ana Bela, Lucas, Susana D., Gonçalves, Lídia M., Correia, Henrique F., Cardote, Teresa A.F., Guedes, Rita C., Iley, Jim, Moreira, Rui
Format: Article
Language:English
Subjects:
Animals
Anti-Inflammatory Agents - chemical synthesis
Anti-Inflammatory Agents - pharmacology
Biological and medical sciences
Cathepsin G
Cathepsin G - antagonists & inhibitors
Cathepsin G - metabolism
elastase
Human neutrophil elastase
Humans
Kinetics
Leukocyte Elastase - antagonists & inhibitors
Leukocyte Elastase - metabolism
mechanism of action
Medical sciences
neutrophils
Oxazolidine-2,4-diones
Oxazolidinones - chemical synthesis
Oxazolidinones - pharmacology
Pancreatic Elastase - antagonists & inhibitors
Pancreatic Elastase - metabolism
Pharmacology. Drug treatments
Porcine pancreatic elastase
proteinase inhibitors
Pseudo-irreversible inhibitors
Serine proteases
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - pharmacology
Structure-Activity Relationship
Swine
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Summary:The synthesis, inhibitory activity and mode of action of oxazolidine-2,4-diones against porcine pancreatic elastase, here used as a model for human neutrophil elastase, are reported. The nature of N-substitution at the oxazolidine-2,4-dione scaffold has large effect on the inhibitory potency against elastase. N-Acyl and N-sulfonyloxazolidine-2,4-diones emerged as potent pseudo-irreversible inhibitors, displaying high second-order rate constants for PPE inactivation. The title compounds were also shown to be potent inhibitors of human neutrophil elastase (HNE) and proteinase-3, and weak inhibitors of human cathepsin G. The results herein presented show that the oxazolidine-2,4-diones represent a new promising class of serine protease inhibitors.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.04.093