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 ketone-based series of 3-amino-6-phenylpyridin-2-ones that had been optimized 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-chlorophenyl)sulfonyl]-carbamoyl]phenyl]sulfonyl. At a 30 min prechallenge interval, compound 9, which incorporates this substituent, had an ED50 of approximately 2 nmol/animal and, qualitatively, afforded a very similar dose-response relationship to that found with a peptidic trifluoromethyl ketone inhibitor, ICI 200,355.
Department of Medicinal Chemistry, ZENECA Pharmaceuticals, Wilmington, Delaware 19897.
P R
PR
Bernstein
B C
BC
Gomes
B J
BJ
Kosmider
E P
EP
Vacek
J C
JC
Williams
D000280:Administration, Inhalation; D000595:Amino Acid Sequence; D000818:Animals; D006224:Cricetinae; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology*; D019272:Leukocyte Elastase; D008171:Lung Diseases / Q000139:chemically induced; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011728:Pyridones / Q000138:chemical synthesis* / Q000494:pharmacology*; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects
D006845:Hydrocarbons, Fluorinated; D007659:Ketones; D009842:Oligopeptides; D011728:Pyridones; D013449:Sulfonamides; C069366:ICI 200355; C069695:ICI 200880; D010196:Pancreatic Elastase; D019272:Leukocyte Elastase