BIOLOGICAL-ACTIVITY OF WIN-63759, AN ORALLY BIOAVAILABLE INHIBITOR OFHUMAN NEUTROPHIL ELASTASE

The proteolytic activity of human neutrophil elastase (HNE) has bt en implicated in a number of pulmonary diseases. We report on the activit y of an orally bioavailable, selective HNE inhibitor, WIN 63759 ethyle thy)3-oxo-1,2-benzisothiazol-2(3H)-yl]methyl 2,6-dichloro-3-[2-(4-morp holinyl)ethoxy] benzoate S,S dioxide. WIN 63759 is a potent inhibitor of HNE (K-i = 14 pM) and is at least 70,000-fold selective for HNE rel ative to other serine proteases or receptors. In vivo, WIN 63759 produ ces dose-related inhibition of HNE-induced pulmonary hemorrhage follow ing either intravenous (ED(50) = 3 mg/kg; 4.5 mu mol/kg) or subcutaneo us (ED(50) = 19 mg/kg; 28.5 mu mol/kg) administration in hamsters. WIN 63759 selectivity inhibits HNE in vivo (relative to chymotrypsin or t rypsin), and is equally efficacious following acute or chronic adminis tration in the hamster. WIN 63759 is not orally bioavailable in hamste rs, rats, or monkeys, and this lack of bioavailability is related to r apid in vitro metabolism in liver, jejunum, or blood. In contrast, WIN 63759 is stable in canine tissues in vitro and is orally bioavailable in dogs. Bioavailability is enhanced in fed relative to fasted dogs. Bronchoalveolar lavage studies indicate that WIN 63759 is present in t he target organ (lung) at concentrations 3-5 x higher than those found in plasma following oral administration of 3-100 mg/kg (4.5-150 mu mo l) in dogs. These data show that WIN 63759 is a potent, selective, and orally bioavailable inhibitor of HNE. Since oral bioavailability was predictable based on in vitro metabolism, and since in vitro metabolis m in humans is similar to that observed with dogs, WIN 63759 and other members of this chemical series may be orally bioavailable inhibitors of neutrophil elastase in man. (C) 1995 Wiley-Liss, Inc.