PHARMACOLOGICAL EVALUATION OF SELECTED, ORALLY-ACTIVE, PEPTIDYL INHIBITORS 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 several chronic infl ammatory diseases. A large series of peptidyl electrophilic ketones ha ve been shown to be potent inhibitors of HNE in vitro and in vivo. We report the pharmacology and pharmacokinetics of selected inhibitors fr om this series. MDL 101,146, MDL 102,111, MDL 102,823 and MDL 100,948A are -Val-Pro-Val-pentafluoroethylketones with various amino-terminal protecting groups. Although their K-i values varied considerably, (25- 170 nM), these compounds demonstrated similar ED(50) values after oral administration in the HNE-induced hemorrhage model in hamsters and ra ts. The duration of action of MDL 102,111 was shorter than that of the other analogs in the HNE-induced pulmonary hemorrhage model in both s pecies. The duration of action of all of the compounds was longer in t he rat than in the hamster. Isolated sections of rat jejunum were used to determine the in situ absorption of these compounds. MDL 102,111 s howed the greatest extent of absorption, with MDL 102,823, MDL 100,948 A and MDL 101,146 following in descending rank order. The comparative metabolic stability of these analogs was measured over a 2-hr incubati on period using rat liver homogenates. MDL 101,146 was the most stable , followed by MDL 102,823, MDL 102,111 and MDL 100,948A. MDL 101,146 w as more stable in a liver homogenate from rats compared with a liver h omogenate from hamsters. The in situ absorption and metabolic stabilit y data are consistent with the results from the HNE-induced hemorrhage model and help to explain the similar potency in vivo of a series of compounds that have varying affinities for HNE in vitro.