| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg |
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| Other Sizes |
Purity: ≥98%
GSK-5498A is a novel, potent and selective small molecule blocker of Calcium-Release Activated Calcium (CRAC) channel with IC50 of 1 uM; It inhibits mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety of species. Loss of function mutations in the two key proteins which constitute Calcium-Release Activated Calcium (CRAC) channels demonstrate the critical role of this ion channel in immune cell function. GSK-5498A was tested to demonstrate their ability to inhibit mediator release from mast cells, and pro-inflammatory cytokine release from T-cells in a variety of species. GSK-5498A completely inhibited calcium influx through CRAC channels. This led to inhibition of the release of mast cell mediators and T-cell cytokines from multiple human and rat preparations. Mast cells from guinea-pig and mouse preparations were not inhibited by GSK-5498A; however cytokine release was fully blocked from T-cells in a mouse preparation. GSK-5498A confirmed the critical role of CRAC channels in human mast cell and T-cell function, and that inhibition can be achieved in vitro. The rat displays a similar pharmacology to human, promoting this species for future in vivo research with this series of molecules. Together these observations provide a critical forward step in the identification of CRAC blockers suitable for clinical development in the treatment of inflammatory disorders.
| Targets |
Calcium-Release Activated Calcium (CRAC) channels [1]
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| ln Vitro |
In human embryonic kidney cells, GSK-5498A (1 and 10 μM) blocks calcium influx through CRAC channels [1]. Using the calcium-sensitive dye Fluo4-AM, GSK-5498A (1 nM-10 μM) suppresses the thapsigargin-induced fluorescence signal in Jurkat cells (pIC50: 6.3) [1]. Cytostim-induced production of interferon-γ and IL-5 in PBMC is inhibited in a concentration-dependent manner by GSK-5498A (1 nM-10 μM) [1]. Rat tissue-resident mast cell degranulation is inhibited by GSK-5498A (1 μM–10 μM) [1]. In mice and rats, GSK-5498A (10 nM–10 μM) suppresses the release of T cell cytokines (IL-2) [1]. CRAC channels are more selectively bound by GSK-5498A (0-10 μM) than by other ion channels, enzymes, or G protein-coupled receptors [1].
1. Calcium influx inhibition: GSK-5498A completely inhibited calcium influx through CRAC channels in immune cells from multiple species [1] 2. Mast cell mediator release inhibition: The drug effectively inhibited mediator release from mast cells isolated from human and rat preparations, while mast cells from guinea-pig and mouse preparations were not inhibited [1] 3. T-cell cytokine release inhibition: GSK-5498A fully blocked the release of pro-inflammatory cytokines from T-cells in human, rat, and mouse preparations [1] 4. Species-specific pharmacology: The pharmacology of GSK-5498A in rats was similar to that in humans, confirming the critical role of CRAC channels in human mast cell and T-cell function [1] |
| Enzyme Assay |
1. CRAC channel calcium influx detection assay: Immune cells (mast cells or T-cells) from human, rat, mouse, or guinea-pig were isolated and seeded in appropriate culture systems. Cells were loaded with a calcium-sensitive fluorescent probe and pretreated with GSK-5498A at specified concentrations. Calcium release was induced by appropriate stimuli to activate CRAC channels. The fluorescence intensity was monitored in real-time to measure calcium influx through CRAC channels, and the inhibitory effect of GSK-5498A was evaluated by comparing the fluorescence signal with the vehicle control group [1]
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| Cell Assay |
1. Mast cell mediator release assay: Mast cells were isolated from the tissues of human, rat, mouse, or guinea-pig. The cells were suspended in culture medium and pretreated with GSK-5498A for a certain period. Mast cell activation was induced by specific stimuli, and the cells were incubated for a specified time. The supernatant was collected, and the amount of released mediators was detected using relevant assay methods to assess the inhibitory effect of GSK-5498A [1]
2. T-cell pro-inflammatory cytokine release assay: T-cells were isolated from the spleen or other immune tissues of different species. The cells were activated with appropriate stimulants under culture conditions and treated with GSK-5498A simultaneously. After incubation for a certain period, the cell culture supernatant was collected. The concentration of pro-inflammatory cytokines in the supernatant was measured using specific detection methods to determine the inhibitory effect of GSK-5498A on cytokine release [1] |
| References | |
| Additional Infomation |
GSK-5498A is a pyrazole compound with the structure 1H-pyrazole, substituted at positions 1 and 3 with 2-fluoro-6-(trifluoromethyl)benzyl and (2,6-difluorobenzoyl)amino groups, respectively. It is a calcium release-activated calcium channel (CRAC) channel inhibitor, capable of inhibiting the release of mast cell mediators and T cell cytokines in humans and rats. It is a calcium channel blocker. It belongs to the pyrazole, secondary amide, difluorobenzene, and (trifluoromethyl)benzene classes of compounds.
1. Drug Classification and Properties: GSK-5498A is a highly selective small molecule CRAC channel blocker[1] 2. Mechanism of Action: This drug inhibits immune cell activation by completely blocking the influx of calcium ions through CRAC channels, which is crucial for mast cell mediator release and T cell pro-inflammatory cytokine production[1] 3. Therapeutic Potential: GSK-5498A is a promising candidate for clinical treatment of inflammatory diseases because it effectively inhibits immune cell activation in vitro[1] 4. Preclinical Study Value: The pharmacological properties of GSK-5498A in rats are similar to those in humans, making this species suitable for future in vivo studies of this series of CRAC channel blockers. [1] |
| Molecular Formula |
C18H11F6N3O
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|---|---|
| Molecular Weight |
399.2899
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| Exact Mass |
399.08
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| CAS # |
1253186-49-0
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| PubChem CID |
46945384
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
403.3±45.0 °C at 760 mmHg
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| Flash Point |
197.7±28.7 °C
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| Vapour Pressure |
0.0±0.9 mmHg at 25°C
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| Index of Refraction |
1.552
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| LogP |
2.62
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
28
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| Complexity |
538
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
AUBGZAJDHUHMAE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H11F6N3O/c19-12-4-1-3-11(18(22,23)24)10(12)9-27-8-7-15(26-27)25-17(28)16-13(20)5-2-6-14(16)21/h1-8H,9H2,(H,25,26,28)
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| Chemical Name |
2,6-difluoro-N-[1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]pyrazol-3-yl]benzamide
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| Synonyms |
GSK-5498A; GSK 5498A; GSK5498A
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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 (~250.44 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 3 mg/mL (7.51 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 30.0 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: ≥ 3 mg/mL (7.51 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 30.0 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 | 2.5044 mL | 12.5222 mL | 25.0445 mL | |
| 5 mM | 0.5009 mL | 2.5044 mL | 5.0089 mL | |
| 10 mM | 0.2504 mL | 1.2522 mL | 2.5044 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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