INHIBITION OF HUMAN NEUTROPHIL ELASTASE WITH PEPTIDYL ELECTROPHILIC KETONES .2. ORALLY-ACTIVE P-G-VAL-PRO-VAL PENTAFLUOROETHYL KETONES

Valylprolylvalyl pentafluoroethyl ketones with different N-protecting groups were evaluated in vitro and in vivo as inhibitors of human neut rophil elastase (HNE). Several of these compounds were found to be ora lly 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 epime rization studies were performed on 71 and related compounds in various media, including human blood serum. Highperformance liquid chromatogr aphy studies on a reversed-phase system as a measure of the Lipophilic ity of 71. and related compounds revealed a small range of relative re tention times wherein the orally active compounds fell. The K-i value determined for 71 vs HNE was 25 nM.