 |
|
Title
|
|
Nonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone.
|
|
|
Authors
|
|
P.R.Bernstein,
B.C.Gomes,
B.J.Kosmider,
E.P.Vacek,
J.C.Williams.
|
|
|
Ref.
|
|
J Med Chem, 1995,
38,
212-215.
|
|
|
PubMed id
|
|
|
|
|
|
Abstract
|
|
|
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.
|
|
|
|