1-Alkoxycarbonyl-3-halogenoazetidin-2-ones as elastase (PPE) inhibitors

A series of 1-alkoxycarbonyl-3-halogenoazetidin-2-ones, designed as potential suicide inhibitors of serine proteases, has been synthesized and evaluated against porcine pancreatic elastase (PPE). All the compounds were transient inhibitors, their activity depending mainly on the nature of the haloge...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2002-12, Vol.10 (12), p.3955-3964
Main Authors: Gérard, Stéphane, Nollet, Gaëtan, Vande Put, Jennifer, Marchand-Brynaert, Jacqueline
Format: Article
Language:English
Subjects:
Analytical, structural and metabolic biochemistry
Animals
Azetidines - chemical synthesis
Azetidines - pharmacology
Biological and medical sciences
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Hydrolases
Hydrophobic and Hydrophilic Interactions
Kinetics
Pancreatic Elastase - antagonists & inhibitors
Serine Proteinase Inhibitors - chemical synthesis
Serine Proteinase Inhibitors - pharmacology
Structure-Activity Relationship
Swine
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Summary:A series of 1-alkoxycarbonyl-3-halogenoazetidin-2-ones, designed as potential suicide inhibitors of serine proteases, has been synthesized and evaluated against porcine pancreatic elastase (PPE). All the compounds were transient inhibitors, their activity depending mainly on the nature of the halogen substituent: bromo- and iodo- derivatives are more active ( K i ∼2–22 μM) than 3-chloroazetidinones ( K i ∼20–150 μM). The lipophilicity of the N-1 substituent appeared to exert a slightly positive effect. All compounds are reversible inhibitors of PPE ( K i ∼2–150 μM).
ISSN:0968-0896
1464-3391
DOI:10.1016/S0968-0896(02)00304-8