YM-244769 di-HCl is a specific, orally bioactive Na+/Ca2+ exchanger (NCX) inhibitor. YM-244769 di-HCl preferentially inhibits NCX3 and inhibits NCX unidirectional outward current (Ca2+ entry mode), with IC50 of 18 nM and 50 nM respectively. YM-244769 di-HCl effectively prevents hypoxia/reoxygenation-induced SH-SY5Y neuronal cell damage. YM-244769 di-HCl also increases urine output and urinary electrolyte excretion in mice.

Physicochemical Properties

Molecular Formula	C26H24CL2FN3O3
Molecular Weight	516.391468048096
Exact Mass	515.117
CAS #	1780390-65-9
Related CAS #	YM-244769 hydrochloride;837424-39-2;YM-244769;838819-70-8
PubChem CID	90488952
Appearance	Off-white to pink solid powder
Hydrogen Bond Donor Count	4
Hydrogen Bond Acceptor Count	6
Rotatable Bond Count	8
Heavy Atom Count	35
Complexity	601
Defined Atom Stereocenter Count	0
SMILES	Cl.Cl.FC1=CC=CC(=C1)COC1C=CC(=CC=1)OC1C=CC(=CN=1)C(NCC1C=CC=C(C=1)N)=O
InChi Key	OCKIUNLKEPKCRE-UHFFFAOYSA-N
InChi Code	InChI=1S/C26H22FN3O3.2ClH/c27-21-5-1-4-19(13-21)17-32-23-8-10-24(11-9-23)33-25-12-7-20(16-29-25)26(31)30-15-18-3-2-6-22(28)14-18;;/h1-14,16H,15,17,28H2,(H,30,31);2*1H
Chemical Name	N-[(3-aminophenyl)methyl]-6-[4-[(3-fluorophenyl)methoxy]phenoxy]pyridine-3-carboxamide;dihydrochloride
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	IC50: 18 nM (NCX3), 68 nM (NCX1), 96 nM (NCX2)[1]
ln Vitro	With IC50 values of 68 ± 2.9, 96 ± 3.5, and 18 ± 1.0 nM, respectively, YM-244769 (0.003-1 μM) suppresses the initial rates of 45Ca2+ absorption into NCX1, NCX2, and NCX3 transfectants in a dose-dependent manner[1]. In SH-SY5Y cells and LLC-PK1 cells, YM -244769 (0.3 or 1 μM) effectively inhibits the hypoxia/reoxygenation-induced release of lactate dehydrogenase (LDH)[1]. The reverse mode-selectivity of YM-244769 is present [1]. In a concentration- and [Na+]-dependent manner, YM-244769 (1 and 10 μM) suppresses NCX current (INCX); its IC50 against the unidirectional outward INCX (Ca2+ entry mode) is 0.05 μM. values have a Hill coefficient of around 1 and are comparable to the bidirectional outward and inward INCX at 100 nM[3]. YM-244769 does not react with trypsin[3].
ln Vivo	In mice, YM-244769 (0.1–1 mg/kg; po; once) has a dose-dependent natriuretic effect and dramatically raises the Ca2+/Cr ratio and urine excretion of Ca2+[2].
Cell Assay	Cell Viability Assay[1] Cell Types: SH-SY5Y cells treated with NCX1 or NCX3 antisense Tested Concentrations: 0.3 and 1 μM Incubation Duration: Experimental Results: Hypoxia/reoxygenation-induced LDH release was Dramatically attenuated: reduction in cell damage was greater in cells treated with NCX3 antisense (by 61%) than in cells treated with NCX1 antisense (by 35%). 0.3 or 1 μM efficiently suppressed the hypoxia/reoxygenation-induced cell damage in SH-SY5Y cells treated with NCX1 antisense more than in those treated with NCX3 antisense.
Animal Protocol	Animal/Disease Models: Wild-type C57BL/6J mice and NCX-KO mice[2] Doses: 0.1, 0.3 and 1 mg/kg Route of Administration: Oral administration, once Experimental Results: Caused a dose-dependent increase (up to approximately 200%) in urine volume and urinary excretion of electrolytes (Na+ , K+ and Cl-). Natriuretic actions were equivalently observed in NCX1-KO and WT, but disappeared in NCX2-KO and double KO.
References	[1]. YM-244769, a Novel Na+/Ca2+ Exchange Inhibitor That Preferentially Inhibits NCX3, Efficiently Protects Against hypoxia/reoxygenation-induced SH-SY5Y Neuronal Cell Damage. Mol Pharmacol. 2006 Dec;70(6):2075-. [2]. Genetic knockout and pharmacologic inhibition of NCX2 cause natriuresis and hypercalciuria. Biochem Biophys Res Commun. 2015 Jan 9;456(2):670-5. [3]. Inhibitory effect of YM-244769, a novel Na+/Ca2+ exchanger inhibitor on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol. 2016 Nov;389(11):1205-1214.

Solubility Data

Solubility (In Vitro)

DMSO: 100 mg/mL (193.65 mM)

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 2.08 mg/mL (4.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (4.03 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	1.9365 mL	9.6826 mL	19.3652 mL
	5 mM	0.3873 mL	1.9365 mL	3.8730 mL
	10 mM	0.1937 mL	0.9683 mL	1.9365 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.