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| Targets |
HERG (human ether-à-go-go-related gene) channels (underlying \(I_{\mathrm{Kr}}\) conductance) (IC50 = 1.4 ± 0.2 μM at 0.1 Hz; IC50 = 5.2 ± 0.2 μM at 1 Hz) [1]
\(I_{\mathrm{Ks}}\) channels (heteropolymers of \(I_{\mathrm{sk}}\)/KvLQT1 protein subunits) (IC50 = 2.6 ± 0.1 μM; IC50 = 3.1 ± 0.2 μM at 10 mM \([K^{+}]_{\mathrm{e}}\)) [1] |
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| ln Vitro |
Azimilide blocked HERG channels expressed in Xenopus oocytes in a concentration-dependent manner. The block was completely reversible within 15 minutes of washout. The concentration-response relationship for HERG tail currents yielded an IC50 of 5.2 ± 0.2 μM and a Hill coefficient ≈ 1 at a stimulation frequency of 1 Hz. [1]
Azimilide blockade of HERG channels was reverse use-dependent. At a lower channel activation frequency (0.1 Hz), the interpolated IC50 was 1.4 ± 0.2 μM. [1] Azimilide block of HERG channels increased with increasing channel activation duration, indicating binding to open channels, as demonstrated by an envelope of tails test. [1] Azimilide did not affect the rate of HERG channel deactivation; deactivation time constants (\( \tau_{\mathrm{deact}} \)) were similar in control (0.33 ± 0.02 s) and in the presence of 2 μM azimilide (0.31 ± 0.02 s). [1] Azimilide block of HERG channels was voltage-independent. With 3 μM azimilide, block was 48.5 ± 2.3% at -20 mV and 51.6 ± 2.4% at 40 mV. [1] Azimilide did not significantly alter the rate of HERG channel inactivation; inactivation time constants were 14.0 ± 0.6 ms (control) and 12.5 ± 0.4 ms (with 3 μM azimilide). The HERG S631A mutant, which inactivates to a lesser extent, showed similar sensitivity to azimilide (IC50 = 2.6 ± 0.4 μM) as wild-type channels. [1] Azimilide blocked native \(I_{\mathrm{Kr}}\) currents in mouse AT-1 cells in a concentration-dependent manner with an IC50 of 1 μM. [1] Azimilide blocked \(I_{\mathrm{Ks}}\) channels expressed in Xenopus oocytes by human \(I_{\mathrm{sK}}\) protein in a concentration-dependent manner, with an IC50 of 2.6 ± 0.1 μM. [1] |
| Enzyme Assay |
HERG channel block in Xenopus oocytes: Two-microelectrode voltage-clamp configuration was used to record currents from Xenopus laevis oocytes injected with cRNA encoding HERG channels. Recordings were performed at 22°C. The control solution contained (in mM): NaCl 96, KCl 2, CaCl2 1.8, MgCl2 1, HEPES 5 (titrated to pH 7.4 with NaOH). In some experiments, KCl was raised to 10 mM. Microelectrodes were filled with 3 M KCl and had resistances of 0.5-0.9 MΩ. HERG currents were evoked by depolarizing pulses from a holding potential, and tail currents were recorded upon repolarization. [1]
\(I_{\mathrm{Kr}}\) current recording in mouse AT-1 cells: Whole-cell voltage-clamp recordings were performed using a List EPC-7 amplifier. AT-1 cells were superfused with HEPES-buffered saline (HBS) containing (in mM): NaCl 132, KCl 4, CaCl2 1.8, MgCl2 1.2, HEPES 10, glucose 10; pH 7.2 at 24-26°C. Microelectrodes (3-7 MΩ) were filled with a solution containing (in mM): KCl 110, K-BAPTA 5, K2ATP 5, MgCl2 1, HEPES 10; pH 7.2. Series resistance was compensated by 40-70%. Cells were held at -40 mV to inactivate sodium and T-type calcium currents. L-type calcium current was blocked with nisoldipine (0.4-1 μM). \(I_{\mathrm{Kr}}\) currents were elicited by depolarizing test pulses. [1] \(I_{\mathrm{Ks}}\) channel block in Xenopus oocytes: Two-microelectrode voltage-clamp was used to record currents from oocytes expressing human \(I_{\mathrm{sK}}\) protein. \(I_{\mathrm{Ks}}\) channels were activated with 15-second depolarizing voltage steps from -80 mV to -10 mV at 45-second intervals. The effects of azimilide were evaluated in the presence of 2 mM and 10 mM \([K^{+}]_{\mathrm{e}}\). [1] |
| Cell Assay |
AT-1 cell preparation and culture: AT-1 cells were propagated in vivo by subcutaneous injection into syngenic host mice (female 2-3 Mo, B6D2F1/J). Tumors were used to isolate and culture AT-1 cells. Prior to voltage-clamp studies, cells were treated with trypsin to detach them from culture dishes and were stored in PC-1 culture medium at 22-24°C. Cells were studied between days 6 and 18 of culture and within 14 hours of isolation. [1]
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| Animal Protocol |
AT-1 cell propagation in vivo:** AT-1 cells were propagated in vivo by subcutaneous injection into syngenic host mice (female 2-3 Mo, B6D2F1/J, Charles River, Wilmington, MA). [1]
AT-1 cell propagation in vivo: AT-1 cells were propagated in vivo by subcutaneous injection into syngenic host mice (female 2-3 Mo, B6D2F1/J, Charles River, Wilmington, MA). [1] |
| References |
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| Additional Infomation |
Azimilide is a class III antiarrhythmic agent that blocks both cardiac delayed rectifier potassium channels, \(I_{\mathrm{Ks}}\) and \(I_{\mathrm{Kr}}\) (HERG). [1]
The relative contribution of \(I_{\mathrm{Ks}}\) versus \(I_{\mathrm{Kr}}\) block by azimilide to its antiarrhythmic action is expected to depend on conditions such as heart frequency, extracellular potassium concentration (\([K^{+}]_{\mathrm{e}}\)), and β-adrenoceptor-mediated tone. At low heart rates, azimilide is expected to prolong action potential duration principally by blocking \(I_{\mathrm{Kr}}\). At elevated heart rates and/or β-adrenoceptor-mediated tone, \(I_{\mathrm{Ks}}\) blockade becomes more important for its action. [1] Unlike many other HERG channel blockers, azimilide exhibits reverse use-dependence, voltage-independent block, and does not accelerate HERG channel inactivation. [1] |
| Molecular Formula |
C23H30CL3N5O3
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|---|---|
| Molecular Weight |
530.875
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| Exact Mass |
529.141
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| CAS # |
149888-94-8
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| Related CAS # |
Azimilide;149908-53-2;Azimilide-d8 dihydrochloride
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| PubChem CID |
60938
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.32g/cm3
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| Boiling Point |
594.9ºC at 760mmHg
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| Flash Point |
313.6ºC
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| LogP |
4.581
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
8
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| Heavy Atom Count |
34
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| Complexity |
677
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
HHPSICLSNHCSNZ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C23H28ClN5O3.2ClH/c1-26-12-14-27(15-13-26)10-2-3-11-28-22(30)17-29(23(28)31)25-16-20-8-9-21(32-20)18-4-6-19(24)7-5-18;;/h4-9,16H,2-3,10-15,17H2,1H3;2*1H
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| Chemical Name |
1-[[5-(4-chlorophenyl)furan-2-yl]methylideneamino]-3-[4-(4-methylpiperazin-1-yl)butyl]imidazolidine-2,4-dione;dihydrochloride
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| Synonyms |
Azimilide Hydrochloride NE-10064 NE10064NE 10064
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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) |
H2O : ~50 mg/mL (~94.18 mM)
DMSO : ~2 mg/mL (~3.77 mM) |
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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 | 1.8837 mL | 9.4183 mL | 18.8366 mL | |
| 5 mM | 0.3767 mL | 1.8837 mL | 3.7673 mL | |
| 10 mM | 0.1884 mL | 0.9418 mL | 1.8837 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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