DISCOVERY AND BIOLOGICAL-ACTIVITY OR ORALLY-ACTIVE PEPTIDYL TRIFLUOROMETHYL KETONE INHIBITORS OF HUMAN NEUTROPHIL ELASTASE

Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMK s) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protectin against the lung da mage induced by human neutrophil elastase (HNE) when the inhibitors we re administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of pep tidyl TFMKs possessing a variety of N-terminal groups, several compoun ds were identified which demonstrated oral activity. Compounds were ev aluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the incre ase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 mu g/hamster). A number of tr ipeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, o r polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O) C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red c ells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. T hus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitor s can be designed which are effective in vivo when administered either orally or intratracheally.