The Design Of Potent And Stable Benzisothiazolone Inhibitors Of Human-Leukocyte Elastase

The lead compound for this SAR study, benzisothiazolone 1a, was a 15 nM inhibitor of HLE, but was unstable in human blood (t(1/2) < 5 min). The introduction of lipophilic substituents at the R(4)-position such as ethyl or isopropyl and modulation of the electrophilicity of the benzisothiazolone carbonyl led to the identification of a potent (K-i(*) = 0.27 nM) and blood stable (t(1/2) = 260 min) inhibitor 2e, WIN 63395.