Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry
| Autor: | Olivia Y. Graebner, Hubert Koester, Simon Michaelis, Lisa von Kleist, Anna K. Schrey, Kathrin Bartho, Mathias Dreger, Friedrich Kroll, Yan Luo, Marén Schlief, Michael Sefkow |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Models Molecular Pharmacology COMT inhibitor Catechol O-Methyltransferase Mass Spectrometry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship 0302 clinical medicine Drug Discovery Hydrolase medicine Transferase Structure–activity relationship Humans Entacapone Cell Proliferation Catechol-O-methyl transferase Tolcapone Dose-Response Relationship Drug Molecular Structure Catechol O-Methyltransferase Inhibitors Hep G2 Cells 030104 developmental biology chemistry Toxicity Molecular Medicine 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 59(10) |
| ISSN: | 1520-4804 |
| Popis: | Structurally related inhibitors of a shared therapeutic target may differ regarding potential toxicity issues that are caused by different off-target bindings. We devised a differential competition capture compound mass spectrometry (dCCMS) strategy to effectively differentiate off-target profiles. Tolcapone and entacapone are potent inhibitors of catechol-O-methyl transferase (COMT) for the treatment of Parkinson's disease. Tolcapone is also known for its hepatotoxic side effects even though it is therapeutically more potent than entacapone. Here, we identified 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) as a possible toxicity-causing off-target of tolcapone, and this protein is not bound by the less toxic COMT inhibitor entacapone. Moreover, two novel compounds from a focused library synthesized in-house, N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide and 5-(3,4-dihydroxy-5-nitrobenzylidene)-3-ethylthiazolidine-2,4-dione, were utilized to gain insight into the structure-activity relationships in binding to COMT and the novel off-target HIBCH. These compounds, especially N(2),N(2),N(3),N(3)-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide, could serve as starting point for the development of improved and more specific COMT inhibitors. |
| Databáze: | OpenAIRE |
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