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| Targets |
IC50: 18 nM (NCX3), 68 nM (NCX1), 96 nM (NCX2)[1]
YM-244769 dihydrochloride specifically targets the sodium-calcium exchanger (NCX), a membrane protein that regulates intracellular Ca2+ levels. It is particularly effective as an inhibitor of the NCX3 isoform, suppressing the unidirectional outward NCX current (the mode that mediates Ca2+ entry in exchange for Na+ efflux).. The compound demonstrates IC50 values of 18 nM, 68 nM, and 96 nM for NCX3, NCX1, and NCX2, respectively, indicating a strong preference for inhibiting NCX3 over the other isoforms.. |
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| 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].
In vitro, YM-244769 dihydrochloride is a potent and selective NCX inhibitor. It inhibits the reverse mode of NCX (Ca2+ influx) with IC50 values of 18 nM, 68 nM, and 96 nM for NCX3, NCX1, and NCX2, respectively.. This data demonstrates that YM-244769 is approximately 3.8-fold more selective for NCX3 over NCX1 and 5.3-fold more selective for NCX3 over NCX2. It is described as an orally active NCX inhibitor. |
| 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].
Specific in vivo activity data for YM-244769 dihydrochloride has not been detailed in the provided search results. As a selective NCX3 inhibitor, it is hypothesized to be neuroprotective in animal models of cerebral ischemia (stroke) and traumatic brain injury, as NCX3 is predominantly expressed in the brain. It may also be studied in models of cardiac arrhythmias and heart failure, where NCX1 is the dominant isoform, but given its higher potency for NCX3, it is more likely studied in the CNS. The compound is orally active, making it suitable for chronic administration studies. |
| Enzyme Assay |
The specific in vitro protocol for NCX inhibition uses a radioactive ⁴⁵Ca2+ uptake assay in cells expressing specific NCX isoforms. CCL39 cells (fibroblasts) are stably transfected with either NCX1, NCX2, or NCX3. The cells are seeded in 24-well plates. To measure the reverse mode of NCX (the Ca2+ entry mode), the cells are pre-incubated with 10 microM ouabain to inhibit the Na+/K+ ATPase and raise intracellular Na+. After 30 minutes, varying concentrations of YM-244769 dihydrochloride (0.1-1000 nM) are added and pre-incubated for 10 minutes. The exchange is initiated by adding ⁴⁵Ca2+ (1 microCi/well) and incubated for 2 minutes. The reaction is terminated by washing the cells three times with ice-cold PBS containing 1 mM EGTA to remove extracellular calcium. The cells are lysed with 0.2 N NaOH, and the radioactivity is counted. The IC50 values (18, 68, 96 nM) are calculated from the inhibition curves..
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| 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. The in vitro cellular assay for YM-244769 dihydrochloride involves the use of primary rat cortical neurons or a neuronal cell line (e.g., SH-SY5Y). Cells are seeded in 96-well black-walled plates and cultured for 7 days. They are then loaded with a fluorescent calcium indicator (e.g., Fluo-4 AM, 5 uM) for 30 minutes at 37degC. The cells are washed, and the plates are placed in a fluorescence plate reader. Baseline fluorescence is measured for 60 seconds. To activate the reverse mode of NCX (Ca2+ entry), the cells are treated with 10 uM ouabain (to inhibit the Na+/K+ ATPase and raise intracellular Na+) for 10 minutes. Varying concentrations of YM-244769 (0.1-1000 nM) are added, and the increase in fluorescence (representing Ca2+ influx) is measured. The IC50 for the inhibition of the ouabain-induced Ca2+ rise is determined from the dose-response curve. |
| 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. An in vivo protocol for YM-244769 dihydrochloride would involve a rat model of transient middle cerebral artery occlusion (tMCAO) to study ischemic stroke. Male Sprague-Dawley rats are anesthetized, and a filament is inserted into the internal carotid artery to occlude the MCA for 60-90 minutes, followed by reperfusion. YM-244769 dihydrochloride is formulated in a suitable vehicle (e.g., 5% DMSO/40% PEG300/5% Tween-80/50% ddH2O) and administered orally (PO) by gavage at doses of 1, 3, and 10 mg/kg, 30 minutes before the onset of ischemia and then daily for 3 days post-ischemia. The primary endpoint is the reduction in infarct volume, measured by TTC (2,3,5-triphenyltetrazolium chloride) staining at 72 hours. Secondary endpoints include neurological deficit scores (e.g., modified Garcia test) and the measurement of intracellular calcium levels in brain tissue using a calcium-specific fluorescent probe. |
| ADME/Pharmacokinetics |
Detailed pharmacokinetic (PK) data for YM-244769 dihydrochloride is not provided. It is described as an orally active compound, indicating it has sufficient oral bioavailability to be effective.. A standard PK study in rats would involve oral (PO) administration (10 mg/kg) and intravenous (IV) administration (1 mg/kg). Blood samples are collected at multiple time points (0-24 h), and plasma concentrations of YM-244769 are quantified by LC-MS/MS. Key parameters, including terminal half-life (T1/2), maximum plasma concentration (Cmax), area under the curve (AUC), and oral bioavailability (F%), would be determined. The compound is likely metabolized by the liver. Its ability to cross the blood-brain barrier (BBB) would be evaluated by measuring brain and plasma concentrations.
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| Toxicity/Toxicokinetics |
Specific toxicological data for YM-244769 dihydrochloride is not available. As an NCX inhibitor that blocks Ca2+ entry, the primary safety concern is the potential for cardiotoxicity, particularly ventricular arrhythmias, and neurotoxicity due to the disruption of intracellular calcium homeostasis. Standard safety assessment would include a 14-day repeat-dose oral toxicity study in rats to determine the maximum tolerated dose (MTD) and the No-Observed-Adverse-Effect Level (NOAEL). Key endpoints would include continuous telemetry monitoring for arrhythmias, serum cardiac troponin I levels, and histopathological examination of the heart and brain. An in vitro hERG (human Ether-à-go-go-Related Gene) channel assay would also be performed.
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| References |
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| Additional Infomation |
YM-244769 dihydrochloride is a research-grade chemical and is not approved for clinical use. It is a potent and selective inhibitor of the sodium-calcium exchanger 3 (NCX3), with IC50s of 18 nM (NCX3), 68 nM (NCX1), and 96 nM (NCX2).. It acts by blocking the reverse mode (Ca2+ entry) of the exchanger. This compound is a valuable tool for studying the role of NCX3 in the central nervous system, particularly in models of cerebral ischemia, traumatic brain injury, and neurodegeneration. It is for research use only.
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| Molecular Formula |
C26H24CL2FN3O3
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|---|---|
| Molecular Weight |
516.391468048096
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| Exact Mass |
515.117
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| CAS # |
1780390-65-9
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| Related CAS # |
YM-244769 hydrochloride;837424-39-2;YM-244769;838819-70-8
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| PubChem CID |
90488952
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| Appearance |
Off-white to pink solid powder
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
35
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| Complexity |
601
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl.Cl.FC1=CC=CC(=C1)COC1C=CC(=CC=1)OC1C=CC(=CN=1)C(NCC1C=CC=C(C=1)N)=O
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| InChi Key |
OCKIUNLKEPKCRE-UHFFFAOYSA-N
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| 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
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| Chemical Name |
N-[(3-aminophenyl)methyl]-6-[4-[(3-fluorophenyl)methoxy]phenoxy]pyridine-3-carboxamide;dihydrochloride
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| HS Tariff Code |
2934.99.9001
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| 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)
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| Solubility (In Vitro) |
DMSO: 100 mg/mL (193.65 mM)
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| 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.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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