Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine
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Acknowledgments
We would like to thank Manoj Desai and Gerry Rhodes for their suggestions on executing the Late INa program.
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2021, Heart Rhythm O2Citation Excerpt :In addition, the drug should not reduce either peak INa or cardiac contractility function. In this context, studies have been focusing on developing next-generation Na+ channel inhibitors that will exhibit increased selectivity for INaL and fulfill all safety concerns.221–226 The current treatment for LQT2 patients is aimed at reducing the incidence of arrhythmia triggers with beta-blockers or terminating the arrhythmia after onset with ICD.
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2020, Cell Stem CellCitation Excerpt :Because wild-type SCN5A is less responsive to mexiletine (Hu et al., 2018; Zhu et al., 2019), we also created pharmacological models of LQT3 by treating two healthy donor hiPSC-CMs (HD.15S1 and HD.113) with veratridine (0.37 μM) to cause persistent activation and ATX-II (0.5 μM) to inhibit inactivation of Nav1.5 (Figure 4A). For comparison, we also tested INaL inhibitors GS945867 (GS-967) (Koltun et al., 2016) and ranolazine. Both are selective blockers of INaL over INaP but are structurally distinct from each other and mexiletine (Zablocki et al., 2016).
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2020, Organic LettersInhibition of voltage-gated Na<sup>+</sup> currents by eleclazine in rat atrial and ventricular myocytes
2020, Heart Rhythm O2Citation Excerpt :For example, the triazolopyridine GS-967 (now known as PRAX-330), a proof-of-concept selective INaL inhibitor with little activity against IKr, has been shown to have an atrial-selective action against action potential duration, postrepolarization refractoriness, and the maximum upstroke velocity of the action potential, although whether the atrial-selective action of the drug extends to fast INa itself remains unclear.24,25 However, the low therapeutic index of GS-967 associated with nonselective effects on a range of neuronal Na+ channel isoforms and high brain penetrance make it unattractive for development as an antiarrhythmic drug.24 In contrast, eleclazine (ELE; formerly GS-6615) is a selective INaL blocker with properties similar to ranolazine that has been reported to be safe and well tolerated and to shorten the QTcF interval in patients with long QT3 syndrome.26,27