THE DESIGN OF POTENT AND STABLE BENZISOTHIAZOLONE INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE

The lead compound for this SAR study, benzisothiazolone 1a, was a 15 n M 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 be nzisothiazolone carbonyl led to the identification of a potent (K-i() = 0.27 nM) and blood stable (t(1/2) = 260 min) inhibitor 2e, WIN 6339 5.