NONPEPTIDIC INHIBITORS OF HUMAN-LEUKOCYTE ELASTASE .6. DESIGN OF A POTENT, INTRATRACHEALLY ACTIVE, PYRIDONE-BASED TRIFLUOROMETHYL KETONE

Further modification of the 3-amino substituent in a trifluoromethyl k etone-based series of 3-amino-6-phenylpyridin-2-ones that had been opt imized for oral activity led to analogs that were potent intratracheal inhibitors in a model of HLE-induced lung damage in the hamster. The best 3-amino substituent for intratracheal activity is [4-[N-[(4-chlor ophenyl) sulfonyl]carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED(5 0) of similar to 2 nmol/animal and, qualitatively, afforded a very sim ilar dose-response relationship to that found with a peptidic trifluor omethyl ketone inhibitor, ICI 200,355.