mdl-101146 and Hemorrhage

A series of P2-modified, orally active peptidic inhibitors of human neutrophil elastase (HNE) are reported. These pentafluoroethyl ketone-based inhibitors were designed using pentafluoroethyl ketone 1 as a model. Rational structural modifications were made at the P3, P2, and activating group (AG) portions of 1 based on structure-activity relationships (SAR) developed from in vitro (measured Ki) data and information provided by modeling studies that docked inhibitor 1 into the active site of HNE. The modeling-based design was corroborated with X-ray crystallographic analysis of the complex between 1 and porcine pancreatic elastase (PPE) and subsequently the complex between 1 and HNE.

Topics: Administration, Oral; Animals; Azetidines; Binding Sites; Cricetinae; Crystallography, X-Ray; Drug Design; Fluorocarbons; Hemorrhage; Humans; Isoquinolines; Ketones; Leukocyte Elastase; Lung Diseases; Models, Molecular; Molecular Conformation; Neutrophils; Oligopeptides; Pancreatic Elastase; Proline; Serine Proteinase Inhibitors; Structure-Activity Relationship; Swine

Valylprolyvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neutrophil elastase (HNE). Several of these compounds were found to be orally active in HNE-induced rat and hamster lung hemorrhage models. The compound with 4-(4-morpholinylcarbonyl)benzoyl as the protecting group, 71 (MDL 101,146), was studied in greater detail. Hydration and epimerization studies were performed on 71 and related compounds in various media, including human blood serum. High-performance liquid chromatography studies on a reversed-phase system as a measure of the lipophilicity of 71 and related compounds revealed a small range of relative retention times wherein the orally active compounds fell. The Ki value determined for 71 vs HNE was 25 nM.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Chromatography, High Pressure Liquid; Cricetinae; Hemorrhage; Humans; Ketones; Leukocyte Elastase; Molecular Sequence Data; Pancreatic Elastase; Rats; Structure-Activity Relationship

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.

Topics: Administration, Oral; Amino Acid Sequence; Animals; Cricetinae; Dose-Response Relationship, Drug; Drug Administration Routes; Fluorocarbons; Hemorrhage; Humans; Leukocyte Elastase; Lung Diseases; Male; Mesocricetus; Molecular Sequence Data; Morpholines; Oligopeptides; Pancreatic Elastase; Sensitivity and Specificity