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| Targets |
- ORM-10103 specifically targets the cardiac sodium/calcium exchanger (NCX), primarily inhibiting the reverse mode of NCX (NCXrev, mediating Ca²⁺ influx). It exhibits an IC₅₀ of ~0.3 μM against canine cardiac NCXrev [1]
- ORM-10103 shows high selectivity for cardiac NCX (NCX1 subtype) with an IC₅₀ of ~0.25 μM against rat cardiac NCXrev; it does not inhibit other cardiac ion channels (e.g., L-type Ca²⁺ channel, Na⁺ channel, Kv11.1 channel) even at concentrations up to 10 μM [2] |
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| ln Vitro |
- Canine cardiac cell experiments (Reference [1]): In isolated canine right ventricular myocytes, ORM-10103 (0.1–1 μM) dose-dependently reduced ouabain-induced early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). At 1 μM, the incidence of EADs decreased from 80% to 20%, and the amplitude of DADs reduced from 50±5 μV to 15±3 μV. Patch-clamp recordings showed ORM-10103 inhibited NCXrev current (INCX(rev)) with an IC₅₀ of ~0.3 μM, without altering L-type Ca²⁺ current (ICa,L) or Na⁺ current (INa) [1]
- Rat ischemic heart experiments (Reference [2]): In isolated rat hearts subjected to ischemia-reperfusion (I/R), ORM-10103 (0.25–1 μM) added to the perfusion buffer reduced the incidence of ventricular premature beats (VPBs) from 65% to 20% (0.5 μM) and shortened the duration of ventricular tachycardia (VT) from 120±15 s to 30±5 s (0.5 μM). It did not significantly change heart rate (HR) or coronary blood flow (CBF) [2] |
| ln Vivo |
- Canine I/R arrhythmia model (Reference [1]): Male beagle dogs (10–12 kg) underwent left anterior descending coronary artery (LAD) ligation (30 min ischemia, 120 min reperfusion). ORM-10103 (0.1–1 mg/kg) was administered intravenously at the start of reperfusion. At 0.3 mg/kg, the incidence of VT decreased from 75% to 25%, and VT duration reduced from 45±8 s to 10±2 s. The drug reached peak plasma concentration at 10 min post-administration, with a pharmacodynamic duration of ~60 min [1]
- Rat ouabain-induced arrhythmia model (Reference [2]): Male Sprague-Dawley rats (250–300 g) received ouabain (10 μg/kg/min, iv) to induce arrhythmias. Pretreatment with ORM-10103 (0.1–0.5 mg/kg, iv) 10 min before ouabain infusion dose-dependently reduced arrhythmia scores (from 4.0±0.5 to 1.0±0.3 at 0.5 mg/kg) and delayed the onset of the first arrhythmia (from 2.5±0.3 min to 5.8±0.6 min at 0.5 mg/kg). No significant bradycardia or hypotension was observed (HR and mean arterial pressure (MAP) changes <10%) [2] |
| Enzyme Assay |
- Radioactive Ca²⁺ uptake assay (Reference [1]): Canine cardiac membrane vesicles were prepared and incubated in a reaction buffer containing 50 mM Tris-HCl (pH 7.4), 100 mM NaCl, 5 μM ⁴⁵CaCl₂, and ORM-10103 (0.01–10 μM) at 37°C for 30 min. The reaction was terminated by filtration, and the radioactivity of the retained vesicles was measured to quantify NCXrev-mediated ⁴⁵Ca²⁺ uptake. ORM-10103 inhibited ⁴⁵Ca²⁺ uptake with an IC₅₀ of ~0.3 μM [1]
- Patch-clamp assay for INCX(rev) (Reference [2]): Whole-cell patch-clamp recordings were performed on primary rat ventricular myocytes. The extracellular solution contained 140 mM NaCl, 5 mM KCl, and 1.8 mM CaCl₂; the pipette solution contained 130 mM CsCl, 10 mM EGTA, and 5 mM MgATP. ORM-10103 (0.05–1 μM) was added to the extracellular solution, and INCX(rev) was recorded at voltage steps from -100 mV to +60 mV. Current amplitudes were normalized to cell capacitance, and the IC₅₀ for INCX(rev) inhibition was ~0.25 μM [2] |
| Cell Assay |
- Canine myocyte action potential recording (Reference [1]): Primary canine ventricular myocytes were cultured on microelectrode arrays. After 30 min incubation with ORM-10103 (0.1–1 μM), ouabain (1 μM) was added to induce EADs/DADs. Action potential duration at 90% repolarization (APD₉₉₀) and EAD/DAD incidence were recorded. At 1 μM, ORM-10103 shortened APD₉₉₀ by 15±3% (avoiding arrhythmogenic APD prolongation) and reduced EAD incidence from 80% to 20% [1]
- Rat myocyte Ca²⁺ transient assay (Reference [2]): Rat ventricular myocytes were loaded with Fura-2 AM (a Ca²⁺ fluorescent probe). ORM-10103 (0.25–1 μM) was added, and Ca²⁺ transient amplitude and spontaneous Ca²⁺ release (a trigger for DADs) were measured by fluorescence microscopy. At 0.5 μM, Ca²⁺ transient amplitude decreased by 20±4%, and spontaneous Ca²⁺ release incidence dropped from 70% to 15% [2] |
| Animal Protocol |
- Canine I/R model (Reference [1]):
1. Model establishment: Male beagles (10–12 kg) were anesthetized, and the LAD was ligated for 30 min (ischemia) followed by 120 min reperfusion. 2. Drug preparation: ORM-10103 was dissolved in physiological saline containing 5% DMSO. 3. Administration: Intravenous injection of ORM-10103 (0.1, 0.3, 1 mg/kg) at reperfusion onset; the vehicle group received 5% DMSO in saline. 4. Monitoring: Continuous ECG recording (to assess arrhythmias), HR and MAP measurement; post-experiment myocardial tissue collection for NCX expression detection [1] - Rat ouabain model (Reference [2]): 1. Model establishment: Male SD rats (250–300 g) were anesthetized, and ouabain (10 μg/kg/min) was infused intravenously to induce arrhythmias. 2. Drug preparation: ORM-10103 was dissolved in physiological saline containing 2% Tween 80. 3. Administration: Intravenous pretreatment with ORM-10103 (0.1, 0.3, 0.5 mg/kg) 10 min before ouabain infusion; the vehicle group received 2% Tween 80 in saline. 4. Monitoring: ECG recording (arrhythmia scoring by Lambeth criteria), blood sample collection post-experiment for liver/kidney function tests [2] |
| Toxicity/Toxicokinetics |
In vivo safety (Reference [1]): In dogs, intravenous administration of ORM-10103 (0.1–1 mg/kg) did not cause significant changes in heart rate (HR) (variance <15%) or mean arterial pressure (MAP) (variance <15%), nor did it cause atrioventricular block or bradycardia. Histopathological examination of myocardial tissue showed no necrosis or inflammation [1] - Toxicity and protein binding (Reference [2]): In rats, ORM-10103 (0.1–0.5 mg/kg, intravenous) had no significant effect on serum ALT, AST, creatinine, or blood urea nitrogen (P>0.05 compared to the control group). Plasma protein binding was 75±5% (measured by ultrafiltration). Acute toxicity tests showed no death at doses up to 10 mg/kg (LD₅₀ >10 mg/kg) [2]
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| References |
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| Additional Infomation |
ORM-10103 is a novel, highly selective NCX inhibitor designed to treat arrhythmias. Its unique mechanism of action is to reduce intracellular Ca²⁺ overload (a key trigger for EADs/DADs) by targeting NCXrev [1, 2]. Unlike conventional antiarrhythmic drugs (e.g., Class III drugs), ORM-10103 does not excessively prolong the action potential duration (APD) or block other ion channels, thus minimizing the risk of arrhythmia [1]. ORM-10103 is currently in preclinical development for ischemic and non-ischemic ventricular arrhythmias and has shown promising efficacy in canine and mouse arrhythmia models [2].
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| Molecular Formula |
C20H16N2O4
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|---|---|
| Molecular Weight |
348.352
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| Exact Mass |
348.111
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| CAS # |
488847-28-5
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| PubChem CID |
17978512
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| Appearance |
White to off-white solid powder
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| LogP |
5.371
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
26
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| Complexity |
477
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
GZONLGPIHCCJOI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H16N2O4/c23-22(24)16-7-11-20(21-13-16)25-17-8-10-19-15(12-17)6-9-18(26-19)14-4-2-1-3-5-14/h1-5,7-8,10-13,18H,6,9H2
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| Chemical Name |
5-nitro-2-[(2-phenyl-3,4-dihydro-2H-chromen-6-yl)oxy]pyridine
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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 |
| 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 : ~250 mg/mL (~717.67 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.97 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (5.97 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 | 2.8707 mL | 14.3534 mL | 28.7068 mL | |
| 5 mM | 0.5741 mL | 2.8707 mL | 5.7414 mL | |
| 10 mM | 0.2871 mL | 1.4353 mL | 2.8707 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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