Discovery and Biological Activity of Orally Active Peptidyl Trifluoromethyl Ketone Inhibitors of Human Neutrophil Elastase
- 1 June 1997
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of Medicinal Chemistry
- Vol. 40 (12) , 1876-1885
- https://doi.org/10.1021/jm960819g
Abstract
Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 μg/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.Keywords
This publication has 16 references indexed in Scilit:
- Nonpeptidic Inhibitors of Human Neutrophil Elastase. 7. Design, Synthesis, and in Vitro Activity of a Series of Pyridopyrimidine Trifluoromethyl KetonesJournal of Medicinal Chemistry, 1996
- Orally Active .beta.-Lactam Inhibitors of Human Leukocyte Elastase. 3. Stereospecific Synthesis and Structure-Activity Relationships for 3,3-Dialkylazetidin-2-onesJournal of Medicinal Chemistry, 1995
- Nonpeptidic Inhibitors of Human Leukocyte Elastase. 6. Design of a Potent, Intratracheally Active, Pyridone-Based Trifluoromethyl KetoneJournal of Medicinal Chemistry, 1995
- Non-peptidic Inhibitors of Human Leukocyte Elastase. 1. The Design and Synthesis of Pyridone-Containing InhibitorsJournal of Medicinal Chemistry, 1994
- Nonpeptidic Inhibitors of Human Leukocyte Elastase. 3. Design, Synthesis, X-ray Crystallographic Analysis, and Structure-Activity Relationships for a Series of Orally Active 3-Amino-6-phenyl-2-pyridinyl Trifluoromethyl KetonesJournal of Medicinal Chemistry, 1994
- Nonpeptidic Inhibitors of Human Leukocyte Elastase. 2. Design, Synthesis, and in vitro Activity of a Series of 3-Amino-6-aryl-2-oxopyridyl Trifluoromethyl KetonesJournal of Medicinal Chemistry, 1994
- Leukocyte elastase inhibition and t-PA-induced coronary artery thrombolysis in dogs: Beneficial effects on myocardial histologyAmerican Heart Journal, 1991
- Biologic Characterization of ICI 200,880 and ICI 200,355, Novel Inhibitors of Human Neutrophil ElastaseAmerican Review of Respiratory Disease, 1991
- Role of Mast Cell and Neutrophil Proteases in Airway SecretionAmerican Review of Respiratory Disease, 1991
- Inhibition of human neutrophil elastase by ICI 200,355European Journal of Pharmacology, 1991