Potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme identified in rat lung

Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively,...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1993-02, Vol.36 (4), p.468-478
Main Authors: Shiosaki, Kazumi, Tasker, Andrew S, Sullivan, Gerard M, Sorensen, Bryan K, von Geldern, Thomas W, Wu-Wong, Jinshyun R, Marselle, Carol A, Opgenorth, Terry J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Amino Acids - chemistry
Analytical, structural and metabolic biochemistry
Animals
Aspartic Acid Endopeptidases - antagonists & inhibitors
Biological and medical sciences
Blood Pressure - drug effects
Cathepsin D - antagonists & inhibitors
Cell Membrane - enzymology
Endothelin-Converting Enzymes
Endothelins - metabolism
Enzymes and enzyme inhibitors
Fundamental and applied biological sciences. Psychology
Humans
Hydrolases
Lung - enzymology
Metalloendopeptidases
Molecular Sequence Data
Molecular Structure
Pepstatins - chemistry
Pepstatins - pharmacology
Protease Inhibitors - chemical synthesis
Protease Inhibitors - chemistry
Protease Inhibitors - pharmacology
Rats
Renin - antagonists & inhibitors
Solubility
Structure-Activity Relationship
Water
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Summary:Two structurally distinct series of potent and selective inhibitors of an aspartyl protease-like endothelin converting enzyme (ECE) activity identified in the rat lung have been developed. Pepstatin A, which potently inhibits the rat lung ECE, served as the basis for the first series. Alternatively, selected renin inhibitors containing the dihydroxyethylene moiety were shown to be inhibitors of rat lung activity. Subsequent modifications improved inhibition of the rat lung ECE while eliminating renin activity. Both series of ECE inhibitors demonstrated a range of selectivity over Cathepsin D. Water-solubilizing moieties were appended onto selected compounds to facilitate in vivo testing. Partial reduction of the pressor response to exogenously administered Big ET-1 was observed with selected rat lung ECE inhibitors.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00056a007