Pharmacology of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N- [3,3,4,4,4-pentafluoro-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 degrading a number of connective tissue macromolecules and has been implicated in the destructive processes associated with a number of chronic inflammatory diseases. N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N- [3,3,4,4,4-pentafluoro-1-(1-methylethyl)-2-oxobutyl]-L-prolinamide (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 vitro was inhibited by MDL 101,146 in a dose-related manner. Intratracheal instillation of HNE into rodents induces acute pulmonary hemorrhage that can be measured by hemoglobin content in the bronchoalveolar fluid. Oral administration of MDL 101,146 to hamsters at 10, 25 and 50 mg/kg before an intratracheal instillation of HNE inhibited pulmonary hemorrhage with an ED50 of 15 mg/kg. The duration of action of MDL 101,146 (50 mg/kg p.o.) for the inhibition of HNE-induced hemorrhage was between 2 and 4 hr. HNE-induced pulmonary hemorrhage was inhibited by a single bolus i.v. injection of MDL 101,146 (ED50 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-induced pulmonary hemorrhage with an ED50 of 0.5 microgram/hamster (5 microgram/kg) and a duration of action of between 6 and 18 hr. MDL 101,146 inhibited HNE-induced pulmonary hemorrhage by 75% when administered as a single 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 potent, versatile compound with potential value in a number of clinical situations in which there is an imbalance between HNE and endogenous inhibitors.