INHIBITION OF HUMAN NEUTROPHIL ELASTASE .3. AN ORALLY-ACTIVE ENOL ACETATE PRODRUG

Several analogs of N-[4-(4-morpholinylcarbonyl)benzoyl]-L-[3,3,4,4,4-pentafluoro-1-(1-methylethyl)-2-oxobutyl]-L-prolinamide (1), in which the chiral center of the P-1 residue has been eliminated, were synthesized and tested as inhibitors of human neutrophil elastase (HNE). Observations made during the course of this work led to the development of a single-step, stereoselective synthesis of E-enol acetate derivatives from HNE inhibitors containing a mixture of epimers at P-1. In, vitro studies, in the presence of added esterase, and F-19 NMR studies, in biological media, indicated that the E-enol acetate derivatives should act as prodrugs in vivo. The ED(50) value for (E)-N-[4-(4-morpholinylcarbonyl)benzoyl]-L-valyl-N-[2-(acetyloxy)-3,3,4,4,4-pentafluoro-1-(1-methylethyl)-1-butenyl]-L-prolinamide (20), when administered orally in the hamster lung hemorrhage model, was 9 mg/kg.