Functionalized N-aryl azetidinones as novel mechanism-based inhibitors of neutrophil elastase.
A functionalized N-aryl azetidinone has been shown to inactivate human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) by an enzyme-mediated process. The inactivation is characterized by the following kinetic constants at pH 8.0 and 37 degrees C: kinact = 0.035 s-1, KI = 1.2 x 10(-4) M for HLE, 0.08 s-1 and 2.7 x 10(-4) M for PPE, respectively. Two parent molecules devoid of the latent leaving group failed to inactivate HLE and PPE and behaved as substrates of these enzymes. A suicide mechanism is postulated involving the formation of an acyl-enzyme and the simultaneous unmasking of a latent quinonimmonium methide ion which irreversibly reacts with an active site nucleophile. Moreover, the inhibitor is still effective at inhibiting elastase preabsorbed onto elastin.
Wakselman
M
M
Centre National de la Recherche Scientifique, Centre d'Etudes et de Recherches de Chimie Organique Appliquée, Laboratoire de Chimie Organique Biologique, Thiais, France.
Joyeau
R
R
Kobaiter
R
R
Boggetto
N
N
Vergely
I
I
Maillard
J
J
Okochi
V
V
Montagne
J J
JJ
Reboud-Ravaux
M
M
D000818:Animals; D001384:Azetidines / Q000494:pharmacology*; D001665:Binding Sites; D004549:Elastin / Q000378:metabolism; D007700:Kinetics; D009504:Neutrophils / Q000201:enzymology*; D010179:Pancreas / Q000201:enzymology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D013552:Swine
D001384:Azetidines; D004549:Elastin; D010196:Pancreatic Elastase