Biological activity of WIN 63759, an orally bioavailable inhibitor of human neutrophil elastase

The proteolytic activity of human neutrophil elastase (HNE) has been implicated in a number of pulmonary diseases. We report on the activity of an orally bioavailable, selective HNE inhibitor, WIN 63759 6-methoxy-4-(1-methylethy)-3-oxo-1,2-benzisothiazol-2(3H)-yl]methyl 2,6-dichloro-3-2-(4-morpholinyl)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 relative to other serine proteases or receptors. In vivo, WIN 63759 produces dose-related inhibition of HNE-induced pulmonary hemorrhage following either intravenous (ED₅₀ = 3 mg/kg; 4.5 μmol/kg) or subcutaneous (ED₅₀ = 19 mg/kg; 28.5 μmol/kg) administration in hamsters. WIN 63759 selectivity inhibits HNE in vivo (relative to chymotrypsin or trypsin), and is equally efficacious following acute or chronic administration in the hamster. WIN 63759 is not orally bioavailable in hamsters, rats, or monkeys, and this lack of bioavailability is related to rapid 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 the 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 μmol) 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 metabolism 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. © 1995 Wiley-Liss, Inc.