Selective indole-based ECE inhibitors: synthesis and pharmacological evaluation
| Autor: | Kentaro Hashimoto, Hideki Tsujishita, Stefan Weigand, Thomas Krahn, Jens-Kerim Ergüden, Johannes-Peter Stasch, Christian Schröder, Stephan Siegel, Michael Brands, Nagahiro Yoshida, Dirk Heimbach |
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| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Indoles Magnetic Resonance Spectroscopy Pharmacology Endothelin-Converting Enzymes Biochemistry Mass Spectrometry Structure-Activity Relationship Oral administration Drug Discovery medicine Structure–activity relationship Aspartic Acid Endopeptidases Myocardial infarction General Pharmacology Toxicology and Pharmaceutics Enzyme Inhibitors chemistry.chemical_classification Indole test Metalloproteinase Molecular Structure Chemistry Organic Chemistry Metalloendopeptidases medicine.disease Blood pressure Enzyme Docking (molecular) Molecular Medicine Chromatography Liquid |
| Zdroj: | ChemMedChem. 1(1) |
| ISSN: | 1860-7179 |
| Popis: | Inhibition of the metalloprotease ECE-1 may be beneficial for the treatment of coronary heart disease, cancer, renal failure, and urological disorders. A novel class of indole-based ECE inhibitors was identified by high throughput screening. Optimization of the original screening lead structure 6 led to highly potent inhibitors such as 11, which bears a bisaryl amide moiety linked to the indole C2 position through an amide group. Docking of 11 into a model structure of ECE revealed a unique binding mode in which the Zn center of the enzyme is not directly addressed by the inhibitor, but key interactions are suggested for the central amide group. Testing of the lead compound 6 in hypertensive Dahl S rats resulted in a decrease in blood pressure after an initial period in which the blood pressure remained unchanged, most probably the result of ET-1 already present. Indole derivative 6 also displays a cardio-protective effect in a mouse model of acute myocardial infarction after oral administration. The more potent chloropyridine derivative 9 antagonizes big-ET-1-induced increase in blood pressure in rats at intravenous administration of 3 mg kg-1. All ECE inhibitors of the indole class showed high selectivity for ECE over related metalloproteases such as NEP and ACE. Therefore, these compounds might have further potential as drugs for the treatment of coronary heart diseases. |
| Databáze: | OpenAIRE |
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