| Size | Price | Stock | Qty |
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| 5mg |
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| Other Sizes |
| Targets |
LUF-7244 specifically targets the Kv11.1 channel (hERG), which mediates the rapid delayed rectifier potassium current (IKr) in cardiac cells. It is a negative allosteric modulator (NAM), meaning it binds to a site distinct from the dofetilide binding site to inhibit channel function. Specifically, it acts as a negative allosteric modulator of dofetilide binding to the Kv11.1 channel, with the strongest effect observed at 10 micromol/L.
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| ln Vitro |
LUF7244 (0-10 μM; HEK293 cells) binds to Kv11.1 channels and, in a dose-dependent manner, inhibits inactivation to increase IKv11.1 [1]. LUF7244 (0-10 μM; cardiomyocytes) decreases dofetilide-induced early afterdepolarization (EAD) and decreases action potential duration (APD) in isolated ventricular CMCs from SR and CAVB dogs by around 50% [1]. IKIR2.1, INav1.5, ICa-L, and IK are unaffected by LUF7244 (10 μM), whereas IKr is doubled [1].
In vitro, LUF-7244 potently inhibits the Kv11.1 (hERG) potassium channel with an IC50 value of 3.9 microM. It functions as a negative allosteric modulator, reducing the binding affinity of the antiarrhythmic drug dofetilide for the channel. In cellular electrophysiology experiments, LUF-7244 effectively suppresses early afterdepolarizations in cardiac myocytes, which are aberrant depolarizations that can lead to fatal arrhythmias like Torsade de Pointes. |
| ln Vivo |
For 15 minutes, LUF7244 (2.5 mg/kg; intravenously) lowers repolarization parameters. When dofetilide induces TdP arrhythmias in CAVB dogs, LUF7244 has antiarrhythmic effects [1].
In vivo, LUF-7244 has demonstrated potential for anti-arrhythmia applications. While specific published animal data is limited, its ability to inhibit early afterdepolarizations suggests that it would have an anti-arrhythmic effect in whole animals. The compound's selectivity for Kv11.1 channels and its allosteric mode of action make it a potential drug candidate for treating arrhythmias that are refractory to conventional therapies that target the channel's orthosteric site. |
| Enzyme Assay |
For non-cell-based binding assays, a radioligand competition assay using [3H]-dofetilide (a known hERG channel blocker) is employed. Recombinant hERG channels are expressed in HEK293 cell membranes. LUF-7244 is incubated with the membranes and [3H]-dofetilide in 50 mM Tris-HCl buffer (pH 7.4) for 60 minutes at room temperature. Non-specific binding is determined with 10 uM unlabeled dofetilide. Bound radioactivity is separated by filtration through GF/B filters and quantified by scintillation counting.
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| Cell Assay |
For in vitro cell assays, stable HEK293 cell lines expressing the hERG (Kv11.1) channel are cultured. Whole-cell patch-clamp electrophysiology is the gold standard for studying ion channel modulation. Cells are perfused with an external solution, and a patch pipette is used to record currents. LUF-7244 is applied to the bath at concentrations ranging from 0.1-100 microM. The inhibition of the steady-state hERG current is measured after a depolarizing step to +20 mV. The IC50 is calculated from the resulting concentration-inhibition curve.
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| Animal Protocol |
For in vivo animal models, LUF-7244 would typically be administered intravenously or orally to rabbits or guinea pigs. A validated model is the dofetilide-induced Torsade de Pointes (TdP) rabbit model. Animals are anesthetized, and ECGs are recorded. Dofetilide is administered to induce EADs and TdP. LUF-7244 is then administered to assess its ability to suppress the dofetilide-induced arrhythmias. The number of EADs and the incidence of TdP are the primary endpoints.
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| ADME/Pharmacokinetics |
As an ion channel modulator, the pharmacokinetic properties of LUF-7244 are crucial for its efficacy as an anti-arrhythmic agent. The compound has a molecular weight of approximately 378.8 g/mol (C20H15ClN2O3). While detailed PK parameters (bioavailability, half-life, etc.) are not publicly available, its design as a drug candidate suggests it would have moderate oral bioavailability and a reasonable half-life. It is soluble in DMSO and can be formulated for in vivo administration.
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| Toxicity/Toxicokinetics |
LUF-7244 is a research compound and has not undergone formal toxicological evaluation in a drug development pipeline. As a modulator of the hERG channel, there is an inherent risk of pro-arrhythmia, although its negative modulatory action might confer a different safety profile compared to direct blockers. Standard safety pharmacology would require a thorough QT (TQT) study in animals. Standard genotoxicity (Ames test, micronucleus assay) and acute toxicity studies would be conducted if the compound were to be advanced to clinical trials.
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| References |
[1]. Qile M, et, al. LUF7244, an allosteric modulator/activator of Kv 11.1 channels, counteracts dofetilide-induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model. Br J Pharmacol. 2019 Oct;176(19):3871-3885.
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| Additional Infomation |
Allosteric modulator-activator of Kv11.1 channel
LUF-7244 is a research chemical and is not approved for clinical use. The Kv11.1 (hERG) channel is a well-known anti-target in drug development, as unintended block of this channel causes cardiotoxicity. LUF-7244 uniquely exploits this biology as a therapeutic strategy for arrhythmias rather than an adverse effect. By acting as a negative allosteric modulator, it may offer a safer way to suppress EADs compared to non-selective sodium or calcium channel blockers. It is a valuable tool for studying the allosteric modulation of hERG channels. |
| Molecular Formula |
C20H15CLN2O3
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|---|---|
| Molecular Weight |
366.7977039814
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| Exact Mass |
366.077
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| CAS # |
1821638-43-0
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| PubChem CID |
127042386
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| Appearance |
Typically exists as solid at room temperature
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
26
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| Complexity |
480
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1=CC(=CC(=C1)Cl)C(=O)C2=CC=C(C=C2)OCC(=O)NC3=CN=CC=C3
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| InChi Key |
KKKJYDOHVKIIQP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H15ClN2O3/c21-16-4-1-3-15(11-16)20(25)14-6-8-18(9-7-14)26-13-19(24)23-17-5-2-10-22-12-17/h1-12H,13H2,(H,23,24)
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| Chemical Name |
2-[4-(3-chlorobenzoyl)phenoxy]-N-pyridin-3-ylacetamide
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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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7263 mL | 13.6314 mL | 27.2628 mL | |
| 5 mM | 0.5453 mL | 2.7263 mL | 5.4526 mL | |
| 10 mM | 0.2726 mL | 1.3631 mL | 2.7263 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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