FunctionalizedN-aryl azetidinones as novel mechanism-based inhibitors of neutrophil elastase

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Abstract
A functionalized N-aryl azetidinone has been shown to inactive 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°C: k max=0.035 s−1, K 1=1.2 × 10 −4 M for HLE, 0.08 s−1 and 2.7 × 10−4 M for PPE, respectively. Two parent molecules devoid of the latent leaving group failed to inactive HLE and PPE and behaved as substrates of these enzymes. A suicide mechanism 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.