Shari L. Eiff

The design of potent and stable benzisothiazolone inhibitors of human leukocyte elastase

Abstract 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 min). The introduction of lipophilic substituents at the R4-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.