Effects of metalloprotease inhibitors on smooth muscle endothelindashconverting enzyme activity
| Autor: | Arco Y. Jeng, Paivi Jaana Kukkola, Joseph L. Balwierczak, Paula Savage |
|---|---|
| Rok vydání: | 1995 |
| Předmět: |
Thiorphan
Swine Rhamnose Stereochemistry Endothelin-Converting Enzymes Biochemistry Muscle Smooth Vascular Structure-Activity Relationship chemistry.chemical_compound Methionine Animals Aspartic Acid Endopeptidases Potency Protein Precursors IC50 Pharmacology chemistry.chemical_classification Endothelin-1 biology Endothelins Phosphoramidon Glycopeptides Metalloendopeptidases Enzyme assay Enzyme Activation Enzyme chemistry Enzyme inhibitor biology.protein Propionates |
| Zdroj: | Biochemical Pharmacology. 49:291-296 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/0006-2952(94)00508-j |
| Popis: | The enzyme responsible for the conversion of exogenous big endothelindash1 to endothelindash1 by porcine coronary arterial smooth muscle has been shown to be a metalloprotease. The potencies of eight metalloprotease inhibitors for this endothelindashconverting enzyme were determined. CGS 25015, CGS 26129, and thiorphan inhibited the enzyme activity monophasically with ic 50 values of 2.6, 2.4, and 190 μM, respectively. In contrast, the data obtained using phosphoramidon as an inhibitor were best fit by a two-site model. The biphasic concentrationdashresponse curve had ic 50 values of 4.6 μM and 2.2 mM. Three analogs of phosphoramidon were also tested for enzyme inhibition. Removal of the rhamnose moiety of phosphoramidon reduced the potency (IC50 = 15 μM), whereas substitution of the rhamnose by ndash[2-(2-naphthyl)ethyl] improved the potency (IC50 = 2.0 μM). These results identify a thiol and a phosphonyl series of compounds as smooth muscle endothelindashconverting enzyme inhibitors. The structure-activity relationships revealed that an aromatic or aliphatic group in the P2′ position or an aromatic group in the P1 position of the inhibitor significantly increased the potency. |
| Databáze: | OpenAIRE |
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