Characterization of CGS 31447, a Potent and Nonpeptidic Endothelin-Converting Enzyme Inhibitor
| Autor: | S. De Lombaert, Paula Savage, D. Delgrande, Arco Y. Jeng, Suraj S. Shetty |
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| Rok vydání: | 1998 |
| Předmět: |
Male
Stereochemistry Endothelin converting enzyme 1 Organophosphonates Tetrazoles Blood Pressure Endothelin-Converting Enzymes In Vitro Techniques Kidney Renal Circulation Rats Sprague-Dawley medicine Animals Aspartic Acid Endopeptidases Humans Protease Inhibitors Chelation Protein Precursors education Pharmacology chemistry.chemical_classification education.field_of_study Endothelin-1 biology Endothelins Metalloendopeptidases Biological activity Endothelin 1 Recombinant Proteins Rats Kinetics Enzyme chemistry Mechanism of action Enzyme inhibitor biology.protein medicine.symptom Cardiology and Cardiovascular Medicine Endothelin receptor Protein Binding |
| Zdroj: | Journal of Cardiovascular Pharmacology. 31:S68-S70 |
| ISSN: | 0160-2446 |
| DOI: | 10.1097/00005344-199800001-00022 |
| Popis: | Optimization of an aminophosphonic acid series of compounds for inhibition of endothelin-converting enzyme (ECE) has led to the discovery of CGS 31447. This compound reversibly inhibited the activity of recombinant human ECE-1 with an IC50 value of 21 nM. The effect of CGS 31447 was not due to nonspecific chelation of the zinc ion at the catalytic center of ECE-1 by the phosphonic acid of the inhibitor. Determination of kinetic parameters of ECE-1 in the presence of 5-15 nM CGS 31447 revealed the competitive nature of the compound; a K1 of 7 nM was obtained. CGS 31447 infused at concentrations of 0.01, 0.1, and 1.0 microM inhibited the mean increase in big ET-1-induced pressor responses in isolated and perfused rat kidneys by 7, 39, and 68%, respectively, compared with the controls. These results demonstrate that CGS 31447 is a potent, reversible, and competitive inhibitor of ECE-1. |
| Databáze: | OpenAIRE |
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