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).
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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 current prevents 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 myocyte, due to hypoxia, is seen following the reperfusion of blood (Vie et al.,. 2009). High intracellular sodium levels from the persistent current results in 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, driven by the high intracellular concentration of sodium exchanging out of the cell with the extracellular calcium moving in (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 effect 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)
F15845 and 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 to 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).