A comparative SAR and computer modeling study of benzisothiazolone, mechanism-based inhibitors with porcine pancreatic and human leukocyte elastase

Distinct differences in the SAR for HLE and PPE inhibition in this class of compounds were observed. For example, larger lipophilic substituents at the benzisothiazolone 4-position afforded inhibitors that were potent against HLE, but inactive against PPE. These findings are consistent with computer models of inhibitor-enzyme complexes built using the X-ray structure coordinates of HLE and PPE. These models show that substituents at the benzisothiazolone 4-position fit into the S1 specificity pocket of the enzyme and that other differences in the SAR can be explained based on the structural differences of HLE and PPE.