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F15845 F15845 (3-(R)-[3-(2-methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5 benzoxathiepine bromhydrate) is a cardiac drug proposed to have beneficial effects for the treatment of angina pectoris, arrhythmias and ischemia by inhibiting the persistent sodium current (Vacher et al., 2009; Pignier et al., 2010). The drug, currently in phase II of clinical trials, targets the persistent sodium current with selectivity and produces minimal adverse effects in current experimental studies (Vacher et al., 2009; Létienne et al. 2009; Vie et al. 2009; Pignier et al. 2010).

Persistent sodium current In the cardiac myocyte, the persistent sodium current corresponds to the delayed inactivation of the major sodium channel Nav1.5 (Létienne et al. 2009). In a functional muscle cell, this sodium channel plays an important role in the propagation of an action potential through the heart. Sodium influx is a key component in the initial depolarisation of the cell, followed by quick inactivation to allow for a plateau phase and calcium influx (Vacher et al., 2009). Persistent sodium currents prevent this normal action potential pattern, resulting in a prolonged action potential and increased sodium levels within the cardiac myocyte (Undrovinas et al., 1999). Under these conditions the heart is more susceptible to damage and malfunctions (Imahashi et al,. 1999). Inhibition of the persistent sodium current is a novel therapeutic target to prevent long term changes in the heart resulting from ischemia (Létienne et al. 2009; Vie et al. 2009). Hypoxia, heart failure and oxygen derived free radicals are all factors believed to activate the persistent sodium current (Vacher et al., 2009). In ischemia, the major damage to the cardiac myocytes is seen during reperfusion (Vie et.al,. 2009). High intracellular sodium levels from the persistent currents results in a high influx of calcium during reperfusion,; leading to calcium overload, hypercontraction and cardiac myocyte death (Vie et al., 2009). The main contributor to this calcium overload is the sodium/calcium exchanger working in reverse mode, driven by the high intracellular concentration of sodium (Imahashi et al. 1999).

Pharmacology F15845 has been shown to selectively inhibit the persistent sodium current of Nav1.5 (Vacher et al,. 2009) exerting cardioprotective effects following ischemia (Létienne et al. 2009; Vie et al. 2009). In vitro testing showed minimal effects of F15845 on other important ion channels of the heart, including major Ca2+ and K+ channels (Vacher et al.,2009). This characteristic is thought to account for the limited affect of F15845 to change other heart parameters such as basal cardiac function, hemodynamic functions and ventricular fibrillation (Vacher et al., 2009; Pignier et al. 2010). F15845 was also shown to exert improved effects when the membrane potential was depolarised (Vacher et al., 2009), by acting on the extracellular side of the channel (Pignier et al., 2010). This effect of the F15845 on the depolarised state of the persistent sodium current renders the drug particularly useful in ischemic conditions when the cardiac cell is depolarised (Vacher et al., 2009)

Actions on angina The F15845 drug has been developed as a potential drug for therapy of angina pectoris (Vacher et al., 2009). Current anti-anginal drugs, aiming to prevent ischemic events resulting from angina, fail to completely relieve symptoms without further cardiovascular effects (Vacher et al., 2009). In addition to F15845 being more selective for the persistent sodium current compared to its counterparts, it has also been shown to inhibit ST segment changes (Vacher et al., 2009) in the canine model of angina (Sugiyama and Hashimoto, 1999).

References Imahashi K et al. (1999). Intracellular sodium accumulation during ischemia as the substrate for reperfusion injury. Circ.res. 84 1401-1406 Létienne R et al. (2009). Myocardial protection by F 15845, a persistent sodium current blocker, in an ischemia-reperfusion model in the pig. Eur J Pharmacol 624 16-22 Vie B et al. (2009). 3-(R)-[3-(2-Methoxyphenylthio-2-(S)-methylpropyl]amino-3,4-dihydro-2H-1,5-benzoxathiepine Bromhydrate (F 15845) Prevents ischemia-induced heart remodeling by reduction of the intracellular Na+ Overload. J Pharmacol Exp Ther 330(3) 696-703 Sugiyama A, Hashimoto K (1999). Antiischaemic effects of CP-060S, an inhibitor of pathologically modified sodium channels, assessed in the canine experimental model of angina pectoris. J CardiovascPharmacol 33 (1): 70–77 Vacher B et al. (2009) F 15845 inhibits persistent sodium current in the heart and prevents angina in animal models. Br J Pharmacol 156 214-225 Pignier C et al. (2010). Selective inhibition of persistent sodium current by F 15845 prevents ischaemia-induced arrhythmias. Br J pharmacol 161 79-91 Undrovinas A et al. (1999). Repolarisation abnormalities in cardiomyocytes of dogs with chronic heart failure: role of sustained inward current. Cell. Mol. Life Sci 55 494-505