Identification of Potential Off-target Toxicity Liabilities of Catechol-O-methyltransferase Inhibitors by Differential Competition Capture Compound Mass Spectrometry

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• 作者：Lisa von Kleist ; Simon Michaelis ; Kathrin Bartho ; Olivia Graebner ; Marén Schlief ; Mathias Dreger ; Anna K. Schrey ; Michael Sefkow ; Friedrich Kroll ; Hubert Koester ; Yan Luo
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4664-4675
• 全文大小：615K
• 年卷期：0
• ISSN：1520-4804

文摘

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<sup>2sup>,N<sup>2sup>,N<sup>3sup>,N<sup>3sup>-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<sup>2sup>,N<sup>2sup>,N<sup>3sup>,N<sup>3sup>-tetraethyl-6,7-dihydroxy-5-nitronaphthalene-2,3-dicarboxamide, could serve as starting point for the development of improved and more specific COMT inhibitors.