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| Targets |
Flindokalner targets potassium channels, specifically acting as a positive modulator of Kv7 channels and an opener of large conductance, calcium-activated (maxi-K) K⁺ channels. By modulating these channels, flindokalner increases potassium conductance, which hyperpolarizes neurons and reduces neuronal excitability. This mechanism underlies its potential neuroprotective effects.
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| ln Vitro |
Kv7.4 and Kv7.5 are inhibited by flindokalner (BMS-204352) (10 μM), with Kis values of 230 and 605 μM, respectively [1]. Flindokalner (1-10 μM) has a dose-dependent inhibition of Ca2+ currents, with a Kd of 6 μM and a Hill coefficient of 1.33. In freshly isolated rat ventricular myocytes, flindokalner directly blocks cardiac L-type Ca2+ channels without influencing BKCa channels or intracellular signaling [2].
In vitro studies demonstrate that flindokalner modulates Kv7 channels in HEK293 cells and acts as an opener of maxi-K channels. The compound's effects on potassium channel activity can be quantified using patch-clamp electrophysiology in cells expressing the target channels. Flindokalner increases the amplitude of potassium currents and shifts the voltage dependence of channel activation to more negative potentials. |
| ln Vivo |
The dose-dependent anxiolytic effects of flindokalner (BMS-204352) (3-30 mg/kg; i.p.) are reported [1]. Male Wistar rats were given shocks as part of a conditioned anxiety model, and Flindokalner (3–60 mg/kg; i.p.) produced anxiolytic effects [1].
Flindokalner has been investigated for its potential neuroprotective effects and cardiovascular applications. By modulating potassium channels, it may reduce neuronal excitability and protect against ischemic injury. The compound has been studied in animal models of stroke and other neurological disorders. Its cardiovascular applications relate to its effects on smooth muscle tone and cardiac electrophysiology. |
| Enzyme Assay |
For non-cellular assays, flindokalner's modulation of potassium channels can be evaluated using lipid bilayer recordings with purified channel proteins or using membrane patches from cells expressing the channels. The compound's effects on channel gating are assessed by measuring single-channel or macroscopic currents in the presence and absence of the compound. Binding studies using radiolabeled ligands can also be used to assess the compound's affinity for the channel.
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| Cell Assay |
In vitro cellular assays for flindokalner involve treating cells expressing Kv7 or maxi-K channels with the compound and measuring potassium currents using patch-clamp electrophysiology. Whole-cell or inside-out patch configurations are used to assess the effects of the compound on channel activity. Concentration-response curves are generated to determine the EC₅₀ for channel modulation.
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| Animal Protocol |
Animal/Disease Models: Female NMRI or male C57 mouse (20-25 g) (anxiety model) [1]
Doses: intraperitoneal (ip) injection: 3, 10, 30 mg/kg Experimental Results: The time spent in the open area was significant and There was a dose-dependent increase in the latency to enter the open field and increased the number of entries into the open field in the zero maze. In vivo animal experiments with flindokalner involve administering the compound to rodent models of neurological or cardiovascular disease. In models of stroke, animals are treated with flindokalner, and infarct size and neurological deficits are assessed. In cardiovascular models, the compound's effects on blood pressure, heart rate, and arrhythmia susceptibility are evaluated. |
| ADME/Pharmacokinetics |
Flindokalner has a molecular weight of 359.70 and a molecular formula of C₁₆H₁₀ClF₄NO₂. It is a solid at room temperature and is typically stored at -20°C. Purity is typically ≥98%. The compound is soluble in DMSO and other organic solvents. It is stable under recommended storage conditions and is protected from light and moisture.
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| Toxicity/Toxicokinetics |
Toxicological data for flindokalner are limited as it is an investigational compound. As a potassium channel modulator, it may have effects on cardiac electrophysiology and blood pressure. Standard laboratory safety precautions should be followed when handling the compound. It is not intended for human therapeutic use.
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| References |
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| Additional Infomation |
Flindokalner (BMS-204352) is an investigational potassium channel modulator that acts as an opener of maxi-K channels and a positive modulator of Kv7 channels. It has been investigated as a neuroprotectant and for cardiovascular applications. The compound is sponsored by Bristol-Myers Squibb and is available from various commercial suppliers for research applications.
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| Molecular Formula |
C16H10CLF4NO2
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|---|---|
| Molecular Weight |
359.7
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| Exact Mass |
359.034
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| Elemental Analysis |
C, 53.43; H, 2.80; Cl, 9.86; F, 21.13; N, 3.89; O, 8.90
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| CAS # |
187523-35-9
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| PubChem CID |
214350
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| Appearance |
White to off-white solid powder
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| Density |
1.5g/cm3
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| Boiling Point |
436.9ºC at 760mmHg
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| Flash Point |
218ºC
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| Vapour Pressure |
7.82E-08mmHg at 25°C
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| Index of Refraction |
1.574
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| LogP |
4.67
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
24
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| Complexity |
503
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| Defined Atom Stereocenter Count |
1
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| SMILES |
ClC1C([H])=C([H])C(=C(C=1[H])[C@@]1(C(N([H])C2C([H])=C(C(F)(F)F)C([H])=C([H])C1=2)=O)F)OC([H])([H])[H]
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| InChi Key |
ULYONBAOIMCNEH-HNNXBMFYSA-N
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| InChi Code |
InChI=1S/C16H10ClF4NO2/c1-24-13-5-3-9(17)7-11(13)15(18)10-4-2-8(16(19,20)21)6-12(10)22-14(15)23/h2-7H,1H3,(H,22,23)/t15-/m0/s1
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| Chemical Name |
(3S)-3-(5-chloro-2-methoxyphenyl)-3-fluoro-6-(trifluoromethyl)-1H-indol-2-one
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| Synonyms |
BMS 204352; BMS-204352; Flindokalner
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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 : ~100 mg/mL (~278.01 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.95 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 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: ≥ 2.5 mg/mL (6.95 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 25.0 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 | 2.7801 mL | 13.9005 mL | 27.8009 mL | |
| 5 mM | 0.5560 mL | 2.7801 mL | 5.5602 mL | |
| 10 mM | 0.2780 mL | 1.3900 mL | 2.7801 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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