Functionalized N-aryl azetidinones as novel mechanism-based inhibitors of neutrophil elastase

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: kmax=0.035 s −1, K1=1.2 × 10 −4M for HLE, 0.08 s −1and 2.7 × 10 −4M 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.