Nonpeptidic Inhibitors of Human Leukocyte Elastase. 6. Design of a Potent, Intratracheally Active, Pyridone-Based Trifluoromethyl Ketone
- 1 January 1995
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 38 (1) , 212-215
- https://doi.org/10.1021/jm00001a028
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.Keywords
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