We describe the discovery of the first selective, potent, and voltage-dependent inhibitor of the late current mediated by the cardiac sodium channel Na V1.5. The compound 3,4-dihydro- N-[(2 S)-3-[(2-methoxyphenyl)thio]-2-methylpropyl]-2 H-(3 R)-1,5-benzoxathiepin-3-amine, 2a (F 15845), was identified from a novel family of 3-amino-1,5-benzoxathiepine derivatives. The late sodium current inhibition and antiischemic effects of 2a were studied in various models in vitro and in vivo. In a rabbit model of ischemia-reperfusion, 2a exhibited more potent antiischemic effects than reference compounds KC 12291, ranolazine, and ivabradine. Thus, after a single administration, 2a almost abolished ST segment elevation in response to a transient coronary occlusion. Further, the antiischemic activity of 2a is maintained over a wide range of doses and is not associated with any hemodynamic changes, contrary to conventional antiischemic agents. The unique pharmacological profile of 2a opens new and promising opportunities for the treatment of ischemic heart diseases.
[Show abstract][Hide abstract] ABSTRACT: Inhibition of cardiac late Na(+) current (late I(Na)) is a strategy to suppress arrhythmias and sodium-dependent calcium overload associated with myocardial ischemia and heart failure. Current inhibitors of this current are unselective and can be proarrhythmic. This study introduces GS967 (6-(4-(trifluoromethoxy)phenyl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridine), a potent and selective inhibitor of late I(Na), and demonstrates its effectiveness to suppress ventricular arrhythmias. The effects of GS967 on rabbit ventricular myocyte ion channel currents and action potentials were determined. Anti-arrhythmic actions of GS967 were characterized in ex vivo and in vivo rabbit models of reduced repolarization reserve and ischemia. GS967 inhibited Anemonia sulcata toxin II (ATX-II)-induced late I(Na) in ventricular myocytes and isolated hearts with IC(50) values of 0.13 and 0.21 micromolar, respectively. Reduction of peak I(Na) by GS967 was minimal at a holding potential of -120 mV but increased at -80 mV. GS967 did not prolong action potential duration or the QRS interval. GS967 prevented and reversed proarrhythmic effects (afterdepolarizations, torsades de pointes) of the late I(Na) enhancer ATX-II and the I(Kr) inhibitor E-4031 in isolated ventricular myocytes and hearts. GS967 significantly attenuated the proarrhythmic effects of methoxamine+clofilium, and suppressed ischemia-induced arrhythmias. GS967 was more potent and effective to reduce late I(Na) and arrhythmias than either flecainide or ranolazine. Results of all studies and assays of binding and activity of GS967 at numerous receptors, transporters and enzymes indicated that GS967 selectively inhibited late I(Na). In summary, GS967 selectively suppressed late I(Na) and prevented and/or reduced the incidence of experimentally-induced arrhythmias in rabbit myocytes and hearts.
Journal of Pharmacology and Experimental Therapeutics 09/2012; 344(1). DOI:10.1124/jpet.112.198887 · 3.97 Impact Factor
"In cardiomyocytes, it is well established that hypoxia constitutes a major trigger of the persistent mode of Nav1.5 channels which in turn leads to Ca 2+ overload (Saint et al., 1992; Saint, 2008). We recently described a new potent Nav1.5 channel blocker, F 15845 (Le Grand et al., 2008; Vacher et al., 2009) that selectively interacts with the persistent sodium current in cardiomyocytes. It is unknown, however, whether blockade of the persistent sodium current mediated by Nav1.5 channels in SMCs can influence the contractility of artery and prevent the development of hypoxia-induced contractures . "
[Show abstract][Hide abstract] ABSTRACT: The persistent sodium current is involved in myocardial ischaemia and is selectively inhibited by the newly described 3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine bromhydrate (F 15845). Here, we describe the pharmacological profile of F 15845 against the effects of hypoxia in femoral arteries in vitro.
Isometric tension measurement of rat isolated femoral arteries was used to characterize the protective effect of F 15845 against contraction of the vessels induced by veratrine (100 microg.mL(-1)) or hypoxia.
Rat femoral artery expressed the Na(v)1.5 channel isoform. When exposed to veratrine (100 microg.mL(-1)), vessels developed a rapid and strong contraction that was abolished by both absence of sodium and blockade of the Na(+)/Ca(++) exchanger by KB-R7943 (10 and 32 micromol.L(-1)) or treatment with F 15845. When used before veratrine exposure, the potency of F 15845 depended on the extracellular K(+) concentration (IC(50)= 11 and 0.77 micromol.L(-1) for 5 and 20 mmol.L(-1) KCl, respectively), whereas its potency was unaffected by extracellular K(+) concentration when given after veratrine. F 15845 did not affect either KCl (80 mmol.L(-1)) or phenylephrine-induced femoral artery contraction. Moreover, endothelium disruption did not affect the protective effect of F 15845 against veratrine-induced femoral artery contraction, suggesting a mechanism of action dependent on smooth muscle cells. Finally, F 15845 prevented in a concentration-dependent manner rat femoral artery contraction induced by hypoxia.
F 15845, a selective blocker of the persistent sodium current prevented vascular contraction induced by hypoxic conditions.
British Journal of Pharmacology 09/2010; 161(2). DOI:10.1111/j.1476-5381.2010.00912.x · 4.84 Impact Factor
"electivity for INap is not optimal ( Antzelevitch et al . , 2004 ) . Furthermore , it is not known whether the anti - arrhythmic activity of ranolazine is due to blockade of INap alone or to a combination of non - selective inter - actions with other targets . We recently described a novel , more selective and potent blocker of INap , F 15845 ( Le Grand et al . , 2008 ; Vacher et al . , 2009 ; Vie et al . , 2009 ) , which is currently entering phase II clinical trials for the treatment of angina . However , the anti - arrhythmic properties of F 15845 during cardiac ischaemia have not yet been fully investigated . Hence , the aims of the present study were , first , to assess the effects of F 15845 on"
[Show abstract][Hide abstract] ABSTRACT: Myocardial ischaemia is associated with perturbations of electrophysiological profile of cardiac myocytes. The persistent sodium current (I(Nap)) is one of the major contributors to ischaemic arrhythmias and appears as an attractive therapeutic target. We investigated the effects of F 15845, a new anti-anginal drug on I(Nap) and in integrative models of I(Nap)-induced arrhythmias.
Sodium current was investigated using patch clamp technique on wild-type and DeltaKPQ-mutated hNav1.5 channels transfected in HEK293 cells. Effects of F 15845 on action potentials (APs) were studied by the glass microelectrode technique and its anti-arrhythmic activities were investigated in ischaemia- and aconitine-induced arrhythmias in the rat.
We demonstrated that F 15845 is a potent blocker of I(Nap) acting from the extracellular side of the channel. Blockade of I(Nap) was voltage dependent and characterized by an almost pure tonic block. F 15845 shortened AP from rabbit Purkinje fibres, confirming its lack of pro-arrhythmic activity, and prevented AP lengthening induced by the I(Nap) activator veratridine. F 15845 did not affect APs from rabbit atria and guinea pig papillary muscle where I(Nap) is not functional, confirming its inability to affect other cardiac ionic currents. F 15845 was effective at preventing fatal ventricular fibrillation and ventricular tachycardia during coronary ligation without modifying heart rate and blood pressure, and dose dependently increased the dose threshold of aconitine required to induce ventricular arrhythmias.
F 15845, a novel anti-anginal drug targeting I(Nap), demonstrates new anti-arrhythmic properties which may be of therapeutic benefit against ischaemia-induced arrhythmias.
British Journal of Pharmacology 09/2010; 161(1):79-91. DOI:10.1111/j.1476-5381.2010.00884.x · 4.84 Impact Factor
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