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| Targets |
The primary target of GLPG2451 is the cystic fibrosis transmembrane conductance regulator (CFTR), a chloride channel that is defective in cystic fibrosis. The most common CFTR mutation is F508del, which results in misfolding and reduced channel activity at the cell surface. GLPG2451 acts as a CFTR potentiator, meaning it enhances the activity of CFTR channels that are already present at the cell surface. It effectively potentiates low temperature-rescued F508del CFTR with an EC₅0 of 11.1 nM. By increasing CFTR channel activity, GLPG2451 helps restore chloride transport in cystic fibrosis patients, thereby reducing mucus accumulation and improving lung function.
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| ln Vitro |
In G551D/F508del cells, GLPG2451's EC50 value is 675 nM, and its effectiveness is 147% that of VX770[1].
In vitro studies have demonstrated that GLPG2451 is a potent and selective CFTR potentiator with an EC₅0 of 11.1 nM for potentiating low temperature-rescued F508del CFTR. The compound enhances the activity of CFTR channels, increasing chloride transport in cells expressing mutant CFTR. GLPG2451 has been shown to be effective in various cell-based assays, including those using primary airway epithelial cells from cystic fibrosis patients. The compound's potency and selectivity make it a promising candidate for the treatment of cystic fibrosis. In vitro studies are used to characterize the compound's mechanism of action and to evaluate its potential for combination therapy with other CFTR modulators. |
| ln Vivo |
In vivo studies of GLPG2451 are focused on evaluating its efficacy in animal models of cystic fibrosis and its potential for clinical development. As a CFTR potentiator, GLPG2451 is expected to improve chloride transport and reduce mucus accumulation in the lungs and other organs. The compound may be studied in combination with CFTR correctors (such as lumacaftor or tezacaftor) to achieve greater restoration of CFTR function. GLPG2451 is a promising candidate for the treatment of cystic fibrosis. Further in vivo studies are needed to evaluate its pharmacokinetic properties, safety, and efficacy in animal models and ultimately in clinical trials.
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| Enzyme Assay |
For in vitro enzyme/receptor binding assays, GLPG2451 is typically evaluated using functional assays that measure CFTR-mediated chloride transport. These assays use cells expressing wild-type or mutant CFTR (such as F508del CFTR) and measure chloride flux using fluorescent indicators (such as SPQ or MQAE) or electrophysiological techniques (such as Ussing chamber or patch-clamp). The compound is incubated with cells at various concentrations, and the potentiation of CFTR activity is measured. EC₅0 values are determined from dose-response curves. Selectivity profiling against other ion channels or transporters may be performed to confirm specificity. Standard assay conditions include physiological buffer systems with appropriate chloride concentrations.
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| Cell Assay |
For in vitro cellular experiments, GLPG2451 is tested in cell lines expressing CFTR, such as CHO or HEK293 cells stably transfected with wild-type or mutant CFTR, or in primary airway epithelial cells from cystic fibrosis patients. Cells are cultured in appropriate media and treated with various concentrations of the compound (typically ranging from picomolar to micromolar). CFTR activity is measured using fluorescent chloride sensors, electrophysiological recordings, or other functional assays. The compound's effects on CFTR trafficking and cell surface expression can be assessed using cell surface biotinylation or immunofluorescence. Cell viability and cytotoxicity are monitored. The compound's activity is typically evaluated in the presence of CFTR correctors to assess potential combination effects.
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| Animal Protocol |
For in vivo animal experiments, GLPG2451 can be administered to animal models of cystic fibrosis, such as CFTR knockout mice or ferrets, via various routes including oral gavage, intravenous injection, or inhalation. The compound's efficacy is evaluated by measuring chloride transport in relevant tissues, such as the airways or intestines. Physiological parameters such as mucus clearance, lung function, and survival are monitored. Pharmacokinetic studies are performed to measure the levels of GLPG2451 in plasma and tissues. The compound's potential for combination therapy with other CFTR modulators may also be evaluated. Animal studies should follow appropriate ethical guidelines and use suitable control groups for comparison.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of GLPG2451 have not been extensively detailed in the public literature. As a small molecule with a molecular weight of 419.38 g/mol, it may have reasonable oral bioavailability and tissue distribution. The presence of fluorine and sulfonamide groups may influence its metabolic stability and clearance. Detailed parameters such as Cₘₐₓ, Tₘₐₓ, AUC, half-life, and clearance would need to be determined through comprehensive PK studies in relevant animal models. The compound's protein binding, metabolism, and excretion pathways remain to be fully characterized. Formulation development may be optimized for in vivo administration, particularly for inhalation or oral delivery.
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| Toxicity/Toxicokinetics |
Toxicological data for GLPG2451 are limited, as the compound is a research tool for CFTR modulation. As a CFTR potentiator, the compound is expected to have a favorable safety profile, but comprehensive toxicology studies would be needed for clinical development. Potential on-target effects related to CFTR potentiation in various tissues should be considered. Off-target effects on other ion channels or transporters should be evaluated. Standard toxicological assessments would include acute and repeated-dose toxicity, genotoxicity, cardiotoxicity (including hERG channel inhibition), and reproductive toxicity. Appropriate safety precautions should be taken when handling this compound, including the use of personal protective equipment and adherence to institutional safety guidelines.
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| References | |
| Additional Infomation |
GLPG2451 is a research compound used to study CFTR biology and develop treatments for cystic fibrosis. No clinical trials or regulatory approvals have been reported for this compound as a therapeutic agent. It is available from various chemical suppliers for research purposes only. The compound is a potent and selective CFTR potentiator that effectively potentiates low temperature-rescued F508del CFTR with an EC₅0 of 11.1 nM. GLPG2451 is a promising candidate for the treatment of cystic fibrosis and may be used in combination with CFTR correctors for enhanced therapeutic efficacy.
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| Molecular Formula |
C16H16F3N3O5S
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| Molecular Weight |
419.3756
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| Exact Mass |
419.076
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| CAS # |
2055015-61-5
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| PubChem CID |
124106089
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| Appearance |
Light yellow to yellow solid powder
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| LogP |
2.1
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
28
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| Complexity |
632
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C1C([H])=C([H])C(=C([H])C=1[H])OC(F)(F)F)(C1C([H])=NC(C(N([H])C([H])([H])[C@]([H])(C([H])([H])[H])O[H])=O)=C(C=1[H])N([H])[H])(=O)=O
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| InChi Key |
UMOGNCVNHXWFIX-VIFPVBQESA-N
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| InChi Code |
InChI=1S/C16H16F3N3O5S/c1-9(23)7-22-15(24)14-13(20)6-12(8-21-14)28(25,26)11-4-2-10(3-5-11)27-16(17,18)19/h2-6,8-9,23H,7,20H2,1H3,(H,22,24)/t9-/m0/s1
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| Chemical Name |
3-amino-N-[(2S)-2-hydroxypropyl]-5-[4-(trifluoromethoxy)phenyl]sulfonylpyridine-2-carboxamide
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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 (~596.12 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.96 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 (4.96 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.96 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3845 mL | 11.9224 mL | 23.8447 mL | |
| 5 mM | 0.4769 mL | 2.3845 mL | 4.7689 mL | |
| 10 mM | 0.2384 mL | 1.1922 mL | 2.3845 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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