A BENZISOTHIAZOLONE CLASS OF POTENT, SELECTIVE MECHANISM-BASED INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE

A new type of mechanism-based inhibitor of human leukocyte elastase (H LE) is described that are designed to inhibit HLE by a suicide route t o form an inhibitor-enzyme complex by cross linking the enzyme active site. A mechanism of HLE inhibition is proposed and was used to design analogues with improved potency. The structure-activity relationships described in this paper are consistent with the proposed mechanism of HLE inhibition, and led to WIN 62785 (12), the most potent compound i n this series with a K-i = 0.3 nM.