Mechanism for slow-binding inhibition of human leukocyte elastase by valine-derived benzoxazinones.
Valine-derived benzoxazinones have been synthesized and found to be competitive, slow-binding inhibitors of human leukocyte elastase (HLE). Steady-state inhibition constants Ki are dependent on aryl substitution and reach a maximum of potency of 0.5 nM with the 5-Cl compound 6. UV-spectral data for the interaction of HLE and the unsubstituted inhibitor 3 indicate that the stable complex formed between enzyme and inhibitor is an acyl-enzyme that can either undergo ring closure, to reform intact benzoxazinone, or hydrolysis, to liberate an N-acylanthranilic acid. "Burst" kinetic data, derived from the direct observation of the interaction of HLE and 3, are consistent with results of the inhibition of catalysis experiments.
D000215:Acylation; D001665:Binding Sites / Q000187:drug effects; D001667:Binding, Competitive; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D007962:Leukocytes / Q000201:enzymology*; D010078:Oxazines / Q000138:chemical synthesis / Q000494:pharmacology*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013997:Time Factors
D004791:Enzyme Inhibitors; D010078:Oxazines; D010196:Pancreatic Elastase