PHARMACOLOGY OF FLUORO-1-(1-METHYLETHYL)-2-OXOBUTYL]-L-PROLINAMIDE (MDL-101,146) - A POTENT ORALLY-ACTIVE INHIBITOR OF HUMAN NEUTROPHIL ELASTASE

Human neutrophil elastase (HNE) is a serine proteinase capable of degr ading a number of connective tissue macromolecules and has been implic ated in the destructive processes associated with a number of chronic inflammatory diseases. fluoro-1-(1-methylethyl)-2-oxobutyl]-L-prolinam ide (MDL 101,146), a potent reversible inhibitor of HNE, was evaluated for its ability to inhibit connective tissue degradation in vitro and in vivo. HNE-mediated degradation of proteoglycan and elastin in vitr o was inhibited by MDL 101,146 in a dose-related manner. Intratracheal instillation of HNE into rodents induces acute pulmonary hemorrhage t hat can be measured by hemoglobin content in the bronchoalveolar fluid . Oral administration of MDL 101,146 to hamsters at 10, 25 and 50 mg/k g before an intratracheal instillation of HNE inhibited pulmonary hemo rrhage with an ED(50) of 15 mg/kg. The duration of action of MDL 101,1 46 (50 mg/kg p.o.) for the inhibition of HNE-induced hemorrhage was be tween 2 and 4 hr. HNE-induced pulmonary hemorrhage was inhibited by a single bolus i.v. injection of MDL 101,146 (ED(50) of 0.5 mg/kg); the duration of action of the compound (10 mg/kg i.v.) was between 60 and 120 min. Intratracheal administration of MDL 101,146 inhibited HNE-ind uced pulmonary hemorrhage with an ED(50) of 0.5 mu g/hamster (5 mu g/k g) and a duration of action of between 6 and 18 hr. MDL 101,146 inhibi ted HNE-induced pulmonary hemorrhage by 75% when administered as a sin gle i.v. bolus after lung hemorrhage had occurred. MDL 101,146 had no effect on thermolysin-induced pulmonary hemorrhage, which demonstrated the specificity of MDL 101,146 for HNE in vivo. MDL 101,146 is a pote nt, versatile compound with potential value in a number of clinical si tuations in which there is an imbalance between HNE and endogenous inh ibitors.