Download MendeleyNonpeptidic inhibitors of human leukocyte elastase. 6. Design of a potent, intratracheally active, pyridone-based trifluoromethyl ketone.
Bernstein, P.R., Gomes, B.C., Kosmider, B.J., Vacek, E.P., Williams, J.C.(1995) J Med Chem 38: 212-215
- PubMed: 7837235
- DOI: https://doi.org/10.1021/jm00001a028
- Primary Citation of Related Structures:
1EAU - PubMed 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.
Organizational Affiliation:
Department of Medicinal Chemistry, ZENECA Pharmaceuticals, Wilmington, Delaware 19897.
