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Purity: ≥98%
Ivacaftor (formerly also known as VX-770; trade name: KALYDECO and Symdeko) is a potent and orally bioactive potentiator of CFTR (cystic fibrosis transmembrane conductance regulator) with potential anti-fibrotic activity. It targets G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM in fisher rat thyroid cells, respectively. Ivacaftor is a drug approved for use in the treatment of cystic fibrosis in people with certain mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, who account for 4–5% cases of cystic fibrosis.
| Targets |
G551D-CFTR (EC50: 100 nM), F508del-CFTR (EC50: 25 nM)
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| ln Vitro |
Ivacaftor (10 µM) boosts the PC secretion activity by 3-fold for ABCB4-G535D, 13.7-fold for ABCB4-G536R, 6.7-fold for ABCB4-S1076C, 9.4-fold for ABCB4-S1176L, and 5.7-fold for ABCB4- G1178S. Ivacaftor corrects the functional deficit of ABCB4 mutants[1]. When compared to R1162X CFTR cells, Ivacaftor (10 μM) dramatically boosts CFTR activity in W1282X-expressing cells[2]. Ivacaftor exhibits no significant activity against 160 targets evaluated including the GABAA benzodiazepine Ivacaftor enhances the chloride secretion with an EC50 of 0.236 ± 0.200 μM, a 10-fold change in potency compared to the F508del HBEs[3]. VX-770 raises the CFTR channel open probability (Po) in recombinant cells for both the G551D gating mutation and the F508del processing mutation. With an EC50 of 25 nM, VX-770 about 6-fold enhances forskolin-stimulated IT in temperature-corrected F508del-FRT cells[4].
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| ln Vivo |
In rats, Ivacaftor (100–200 mg/kg, po) has good oral bioavailability[3].
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| Enzyme Assay |
Membrane Potential Optical Assay for Detecting F508del-CFTR Potentiator Activity [3]
To identify potentiators of F508del-CFTR, an HTS assay format utilizing fluorescent voltage sensing probes was developed using a FLIPR III fluorescence plate reader. NIH-3T3 cells stably expressing F508del-CFTR were incubated for 16–24 h at 27 °C to correct the misfolded F508del-CFTR. Cells are then washed with a bath solution (160 mM NaCl, 4.5 mM KCl, 2 mM CaCl2, 1 mM MgCl2, 10 mM HEPES, pH 7.4 with NaOH) and treated with fluorescent voltage sensing dyes combined with test compounds (or DMSO vehicle control) for 30 min at room temperature. The assay is run on FLIPR III using a single liquid addition step of Cl– free bath solution containing forskolin. Detected changes in membrane potential are due to the potentiator activity of test compounds on Cl– anion flux through F508del-CFTR. |
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| Cell Assay |
Ussing Chamber Recordings [3]
All cells were grown on Costar Snapwell cell culture inserts maintained at 37 °C, unless otherwise indicated, prior to recording. The cell culture inserts were mounted into an Ussing chamber (VCC MC8) to record ISC in the voltage-clamp mode (Vhold = 0 mV). For measurement of ISC, the basolateral bath solution contained the following (in mM): 135 NaCl, 1.2 CaCl2, 1.2 MgCl2, 2.4 K2HPO4, 0.6 KH2PO4, 10 N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid (HEPES), and 10 dextrose (titrated to pH 7.4 with NaOH). The apical NaCl was replaced by equimolar Na+ gluconate (titrated to pH 7.4 with NaOH). For HBE cells, the ISC was measured in the presence of a basolateral to apical Cl– gradient. The normal Cl– solution contained the following (in mM): 145 NaCl, 0.83 K2HPO4, 3.3 KH2PO4, 1.2 MgCl2, 1.2 CaCl2, 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH). The low Cl– solution contained the following (in mM): 145 Na gluconate, 1.2 MgCl2, 1.2 CaCl2, 10 glucose, 10 HEPES (pH adjusted to 7.35 with NaOH). The ISCs were digitally acquired using Acquire and Analyze software. [3] cAMP Measurements[3] The total cAMP concentration (cellular and secreted) in FRT cells following test compound application was determined using a cAMP-Screen 96-well immunoassay system according the manufactures directions. Briefly, FRT cells were incubated for 15 min with test compound and then lysed and transferred to a 96-well assay plate provided with the kit. The plate was incubated at room temperature for 1 h after which it was developed and luminescence emission was measured using the Acquest 384.1536 by LJL Biosystems. The cAMP concentrations were determined using a cAMP standard curve present in each plate. |
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| References |
[1]. Delaunay JL, et al. Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). Hepatology. 2017 Feb;65(2):560-570
[2]. Mutyam V, et al. Therapeutic benefit observed with the CFTR potentiator, ivacaftor, in a CF patient homozygous for the W1282X CFTR nonsense mutation. J Cyst Fibros. 2017 Jan;16(1):24-29 [3]. Hadida S, et al. Discovery of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, ivacaftor), a potent and orally bioavailable CFTR potentiator. J Med Chem. 2014 Dec 11;57(23):9776-9 [4]. Van Goor F, et al. Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770. Proc Natl Acad Sci U S A. 2009 Nov 3;106(44):18825-30. |
| Molecular Formula |
C24H28N2O3
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| Molecular Weight |
392.49
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| Exact Mass |
392.209992
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| Elemental Analysis |
C, 73.44; H, 7.19; N, 7.14; O, 12.23
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| CAS # |
873054-44-5
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| Related CAS # |
Ivacaftor-d9;1413431-07-8;Ivacaftor-d4;Ivacaftor benzenesulfonate;1134822-09-5;Ivacaftor hydrate;1134822-07-3;Ivacaftor-d19;1413431-22-7;Ivacaftor-d18;1413431-05-6
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| Appearance |
White to off-white solid
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| LogP |
5.6
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| tPSA |
78.4Ų
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| SMILES |
O=C(C1=CNC2=C(C=CC=C2)C1=O)NC3=CC(O)=C(C(C)(C)C)C=C3C(C)(C)C.
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| InChi Key |
PURKAOJPTOLRMP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H28N2O3/c1-23(2,3)16-11-17(24(4,5)6)20(27)12-19(16)26-22(29)15-13-25-18-10-8-7-9-14(18)21(15)28/h7-13,27H,1-6H3,(H,25,28)(H,26,29)
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| Chemical Name |
N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide
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| Synonyms |
VX770; Ivacaftor; VX 770; VX-770; Trade name: KALYDECO.
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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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.37 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 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 (6.37 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. View More
Solubility in Formulation 3: 2.5 mg/mL (6.37 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5478 mL | 12.7392 mL | 25.4784 mL | |
| 5 mM | 0.5096 mL | 2.5478 mL | 5.0957 mL | |
| 10 mM | 0.2548 mL | 1.2739 mL | 2.5478 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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