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 (INCX) with IC50 values of ~0.1 μM. Also, it suppresses the unidirectional outward INCX (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.