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
Rok vydání: 2016
Předmět:
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