YM-244769 is a Selective and Orally Active NCX Inhibitor

By Edward Jenner 2022-08-25 #arrhythmia, #heart disease, #intracellular calcium overload, #NCX, #YM-244769

Na⁺/Ca²⁺ exchanger (NCX) is an ion transporter that is important in regulating intracellular Ca²⁺ homeostasis in various tissues. It exchanges Na⁺ and Ca²⁺ in either the Ca²⁺ exit or Ca²⁺ entry mode. The three subtypes of NCX, NCX1, NCX2, and NCX3, are mainly expressed in the heart, brain, and skeletal muscle, respectively. In the case of heart disease, including arrhythmia and hypertrophy, NCX would cause an overload of intracellular Ca²⁺. Therefore, the inhibition of NCX is useful to avoid Ca²⁺overload. According to the research, NCX inhibitors can block the Ca²⁺ entry mode of NCX and reduce the arrhythmogenic consequences of Ca²⁺ overload. At present, there are several NCX inhibitors have been developed.

YM-244769 is one of these NCX inhibitors, which is selective and orally active.

YM-244769 inhibits the bidirectional outward and inward NCX current (I_NCX) with IC₅₀ values of ~0.1 μM. Also, it suppresses the unidirectional outward I_NCX (Ca²⁺ entry mode) (IC₅₀ = 50 nM). Especially, the inhibitor has a preference that preferentially inhibits intracellular Na⁺-dependent ⁴⁵Ca²⁺ uptake via NCX3. Except for heart disease, YM-244769 has neuroprotective activity with efficient protection against hypoxia/reoxygenation-induced SH-SY5Y neuronal cell damage. Besides, compared with other NCX inhibitors, YM-244769 has higher inhibitory potency than KB-R7943 and SN-6, while is similar to SEA0400.

In addition, YM-244769 also shows favorable activity in vivo. In wild-type C57BL/6J mice, YM-244769 (0.1-1 mg/kg; p.o.; single dosage) caused a dose-dependent increase in urine volume and urinary excretion of electrolytes (Na⁺, K⁺, and Cl⁻) (even up to approximately 200%). The NCX inhibitor not only exhibits higher natriuretic action than Trichlormethiazide, but also significantly increases urinary excretion of Ca²⁺ as well as Ca²⁺/Cr ratio.

In conclusion, YM-244769 is a selective and orally active NCX inhibitor, avoiding intracellular calcium overload and possessing neuroprotective activity.

Reference:

[1] Yamashita K, et al. Naunyn Schmiedebergs Arch Pharmacol. 2016 Nov;389(11):1205-1214.

[2] Gotoh Y, et al. Biochem Biophys Res Commun. 2015 Jan 9;456(2):670-5.

[3] Iwamoto T, et al. Mol Pharmacol. 2006 Dec;70(6):2075-83.