title: N-Acyl and N-sulfonyloxazolidine-2,4-diones are pseudo-irreversible inhibitors of serine proteases.
abstract: 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.
authors.affiliation: Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal.
authors.forename: Ana Bela
authors.initials: AB
authors.lastname: Santana
authors.forename: Susana D
authors.initials: SD
authors.lastname: Lucas
authors.forename: Lídia M
authors.initials: LM
authors.lastname: Gonçalves
authors.forename: Henrique F
authors.initials: HF
authors.lastname: Correia
authors.forename: Teresa A F
authors.initials: TA
authors.lastname: Cardote
authors.forename: Rita C
authors.initials: RC
authors.lastname: Guedes
authors.forename: Jim
authors.initials: J
authors.lastname: Iley
authors.forename: Rui
authors.initials: R
authors.lastname: Moreira
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D056649:Cathepsin G / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023303:Oxazolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000893:Anti-Inflammatory Agents; D023303:Oxazolidinones; D015842:Serine Proteinase Inhibitors; D056649:Cathepsin G; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase