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.