IndraLab
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Dofetilide inhibits KCNH2. 119 / 142
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"Drugs illustrating this could include verapamil (hERG + calcium block), ranolazine (hERG + late sodium block), and some of the human immunodeficiency virus (HIV) protease inhibitors such as lopinavir and ritonavir, which block hERG, late sodium, and calcium.19 Amiodarone and its metabolite cause potent hERG block and QTc prolongation, often> 60-90 ms; however, it has been associated with a low risk of TdP despite its profound effects on repolarization, probably because it also blocks both late sodium and calcium currents.19 Thus, late sodium and calcium block shorten the action potential duration of ventricular cells20 (and QTc13, 14, 15); and, in the presence of QTc prolongation, blockage of these inward currents can prevent the initiation of TdP.21 Other evidence of the importance of late sodium current block in preventing TdP comes from a canine model of TdP, where coadministration of mexiletine, a late sodium current blocker, reduced QTc prolongation and the number of TdP events associated with sotalol, a predominant hERG blocker.16 In addition, previous clinical studies have demonstrated that mexiletine can mitigate QTc prolongation caused by the strong hERG blocker quinidine.13, 14, 15 This has been confirmed in recent clinical studies demonstrating that late sodium current blockers (mexiletine, lidocaine) can reduce drug induced QTc prolongation caused by the selective hERG blocker dofetilide,22 and also that mexiletine can mitigate recurrent TdP caused by the acquired long QT syndrome.18 Because there is now a comprehensive understanding of the ionic currents that play a role in QTc prolongation and the development of TdP, the CiPA initiative proposes a new mechanistic, model informed approach to cardiac safety assessment of new drugs."
eidos
"This study investigated hERG block by cisapride , dofetilide , terfenadine , sotalol , and E-4031 - positive controls commonly used to demonstrate assay sensitivity - using the manual whole cell patch clamp method and an action potential-like voltage protocol presented at 0.2 Hz ."
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"Under this paradigm, it will be important to differentiate QTc prolonging drugs with balanced ion channel effects, such as ranolazine (i.e. hERG potassium channel and late sodium current block), that are not associated with torsade from selective hERG potassium channel blockers, such as dofetilide, that are associated with torsade."
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"Imipramine a known Eag blocker induces apoptosis in acute myeloid leukaemia cells via the caspase-3 activation [XREF_BIBR] while it has been shown that HERG expressing cells are more sensitive to apoptosis induced by hydrogen peroxide, with reversal of effect on blocking with a HERG blocker dofetilide [XREF_BIBR]."
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"While nonclinical studies have suggested that late sodium current block can reduce dispersion of repolarization from hERG block, we observed that ranolazine still had a dose dependent relationship with T wave morphology, in some cases having greater T wave morphology changes at equivalent amounts of QTc prolongation compa red with the pure hERG blocker dofetilide."
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"In this context, the results obtained in our
study are not surprising, since the KCNT1 antagonists herein reported
do not present basic nitrogens (CPK16 and CPK20) or their nitrogens have low pK values
(CPK4, CPK13, and CPK18—Jaguar
predicted pK values: 4.48, 5.76, and
5.28, respectively) compared to the nitrogens
of hERG blockers such as quinidine, astemizole, cisapride, and dofetilide."
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"Cells prepared from normal cultures and following cryopreservation were compared with regard to time course of Rb+ efflux response at different concentrations of KCl, overall cell morphology, signal-to noise assay window, assay robustness, and 50% inhibitory concentration (IC50) of the hERG blocker dofetilide."
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"We recently developed a detailed kinetically based model of the hERG blocker dofetilide by extending the consensus five-state Markov chain model that includes three closed states (C 3, C 2 and C 1), a conducting open state and (O) an inactivation state (I) [XREF_BIBR, XREF_BIBR, XREF_BIBR, XREF_BIBR]."
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"As expected, hERG channel inhibitors such as sotalol, dofetilide, quinidine, and ranolazine caused a dose-related FPD prolongation independently from their classifications, confirming findings reported in previous studies (Blinova et al., 2017; Kanda et al., 2018; Millard et al., 2018)."
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"Use dependence can also be produced by a combination of allosteric modulation and gated access, as with lidocaine block of voltage-gated Na channels (Nguyen et al., 2019; Hille, 1977; Vedantham and Cannon, 1999) or dofetilide block of hERG K channels (Wang et al., 2016; Wu et al., 2015; Ficker et al., 1998)."
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"For example, a study utilizing MEA was conducted to examine the dose-dependent effects of dofetilide (a class III antiarrhythmic drug and selective blocker of the hERG channel) and quinidine (a class IA antiarrhythmic drug and blocker of the I current), two compounds associated with arrhythmic beating."
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"Phα1β caused only discreet inhibition (13.55%) of hERG channel activity at 900
pM, with an IC50 > 900 pMol (Figure 1 A)
In contrast, dofetilide, a known hERG antagonist used as a positive control,
caused concentration-dependent blockade of the hERG channel, with a maximal
inhibition of 80.6% at 10 µM and an IC of 0.1642 ± SD (Figure 1 B)."
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"In order to test the hypothesis that determinants of hERG activators might interact with hERG blockers, we mutated F557 and analysed the inhibition of potassium currents through mutant F557L by six " gold standard " hERG blockers dofetilide, haloperidol, terfenadine, astemizole, cisapride and amiodarone."
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"Of note, the similar levels of hERG potassium channel block induced by 2-3 nM dofetilide and 6.9 muM ranolazine (approximately 52%) induced> 200 ms of APDc and FPDc prolongation and multiple arrhythmic events in dofetilide treated cells, but only APDc and FPDc prolongation (< 150 ms) without arrhythmias in ranolazine treated cells."
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"Moreover, studies on hERG1 blockers such as quinidine, dofetilide, and terfenadine have unexpectedly shown that cation-pi interactions in the hERG1 induced block are not critical determinants in channel block implying that pi stacking of the aromatic residues with the drugs is the major contributing factor."