6-acylamino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3-diones mechanism-based inhibitors of human leukocyte elastase and cathepsin G: effect of chirality in the 6-acylamino substituent on inhibitory potency and selectivity Original Research Article

Inhibition of human leukocyte elastase(HLE) by a series of 6-acylamino-2-[(ethylsulfonyl)oxy)]-1H-isoindole-1,3-diones was determined and compared to their inhibition of ChT, PPE, and Cat G. The best inhibitor of the series was 6-((1′S)-camphanyl)amino-2-[(ethylsulfonyl)oxy]-1H-isoindole-1,3-dione 5b, with a kobs/[I]=11,000 M−1 s−1. This study revealed that HLE shows a preference for the S stereochemistry and tolerates hydrophobic substituents in the Sn′ binding sites. Molecular modeling of noncovalent HLE–inhibitor complexes was used as a tool to investigate our binding model. Buffer stability assays reveal that these compounds are susceptible to hydrolysis at physiological pH.