title: Functionalized N-aryl azetidinones as novel mechanism-based inhibitors of neutrophil elastase.
abstract: 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.
authors.affiliation: Centre National de la Recherche Scientifique, Centre d'Etudes et de Recherches de Chimie Organique Appliquée, Laboratoire de Chimie Organique Biologique, Thiais, France.
authors.forename: M
authors.initials: M
authors.lastname: Wakselman
authors.forename: R
authors.initials: R
authors.lastname: Joyeau
authors.forename: R
authors.initials: R
authors.lastname: Kobaiter
authors.forename: N
authors.initials: N
authors.lastname: Boggetto
authors.forename: I
authors.initials: I
authors.lastname: Vergely
authors.forename: J
authors.initials: J
authors.lastname: Maillard
authors.forename: V
authors.initials: V
authors.lastname: Okochi
authors.forename: J J
authors.initials: JJ
authors.lastname: Montagne
authors.forename: M
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: 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
chemical_list: D001384:Azetidines; D004549:Elastin; D010196:Pancreatic Elastase