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      "text": "Paper explains why histamine receptor antagonists are uniquely prone to hERG channel liability",
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      "text": "Given the close structural similarity between the histamine receptor and the hERG channel, a histamine receptor antagonist like terfenadine or pitolisant has inherent off-target activity with hERG – that is, cardiotoxicity is a feature not a bug.",
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      "text": "The clinical and drug chemistry literature is unequivocal – “the reason for this is that the pharmacophores of the hERG channel and histamine receptor show remarkable similarities.” A pharmacophore is a molecular model that characterizes how a drug binds to a receptor. Given the close structural similarity between the histamine receptor and the hERG channel, a histamine receptor antagonist like terfenadine or pitolisant has inherent off-target activity with hERG – that is, cardiotoxicity is a feature not a bug.",
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      "text": "A number of drug discovery and development programs have been hampered by issues with drug induced cardiac arrhythmia. This is particularly well-known for histamine receptor antagonists, e.g., the potent human ether-à-gogo-related gene (hERG) channel blocker Terfenadine (Teldane®, Seldane®). Terfenadine is an H1 receptor 1996; Fenichel et al., 2004; Gintant et al., 2011), but hERG channel blockade has become the most frequent single cause for drug withdrawals (Fenichel et al., 2004), and many drug discovery programs have been delayed (imposing significant costs on the pharmaceutical company) or stopped due to hERG channel liabilities of potential drug candidates. Bahl et al., 2012; Becknell et al., 2012; Hudkins et al., 2012; Moorthy et al., 2014). While compounds from very different chemical classes may interact with the hERG channel due to its relatively large hydrophobic pore, the property of hERG channel liability has been observed especially often for histamine receptor antagonists. The reason for this is that the pharmacophores of the hERG channel and the histamine receptor show remarkable similarities (Davenport et al., 2010).",
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      "text": "Early identification of hERG liability in drug discovery programs by automated patch clamp",
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      "text": "“the reason for this is that the pharmacophores of the hERG channel and histamine receptor show remarkable similarities.” — Davenport et al., 2010",
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      "text": "Source: https://www.frontiersin.org/articles/10.3389/fphar.2014.00203/full",
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      "text": "Pitolisant’s cardiotoxicity and hERG/QT liability is not a surprise, for the same reason that Seldane and astemizole were recalled: drugs in the histamine receptor class are known to be the most prone to hERG channel interference and therefore uniquely dangerous.",
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