Ivacaftor

SKU: orb1305294

Description

Ivacaftor (VX-770) is a CFTR potentiator effective on G551D and F508del mutants, with EC50 values of 100 nM and 25 nM, respectively, in Fisher rat thyroid cell assays. It is a key research tool for studying CFTR channel function and rescue in cellular models of cystic fibrosis, supporting both in vitro and preclinical in vivo research.

Research Area

Cell Biology, Pharmacology & Drug Discovery

Key Properties

• CAS Number: 873054-44-5
• MW: 392.49
• Purity: 99.98% (May vary between batches)
• Formula: C₂₄H₂₈N₂O₃
• SMILES: C(C)(C)(C)C1=C(NC(=O)C=2C(=O)C=3C(NC2)=CC=CC3)C=C(O)C(C(C)(C)C)=C1
• Target: CFTR,Autophagy
• Solubility: H2O:< 1 mg/mL (insoluble or slightly soluble);Ethanol:< 1 mg/mL (insoluble or slightly soluble);DMSO:252 mg/mL (642.05 mM);10% DMSO+40% PEG300+5% Tween 80+45% Saline:5 mg/mL (12.74 mM)

Bioactivity

• Target IC50:
  F508del CFTR:25 nM(EC50, Fisher rat thyroid cells)|CFTR (G551D):100 nM(EC50, Fisher rat thyroid cells)
• In Vivo:
  In a rat dose proportionality study, the AUC and Cmax were increased linearly after oral administration of Ivacaftor in a suspension vehicle at doses from 1 to 200 mg/kg (3, 10, 30, and 100 were the intermediate doses). A similar trend was observed in beagle dogs increasing the oral dose from 3 to 80 mg/kg (10, 30, and 60 were the intermediate doses), confirming high levels of oral absorption. The predicted human hepatic clearance of Ivacaftor using allometric scaling from four species was 4.7 mL min 1 kg 1, which is approximately 23% of hepatic blood flow .
• In Vitro:
  VX-770 increased the forskolin-stimulated IT in temperature-corrected F508del-FRT cells by ~6-fold with an EC50 of 25 ± 5 nM. Before the addition of VX-770, the CFTR channel was exposed to maximally effective concentrations of PKA (75 nM) and ATP (1 mM). Under these conditions, 10 μM VX-770 increased the Po of G551D CFTR by ~6-fold . HEK293 cells transiently expressing ABCB4-wt or the mutants were treated with 10 μmol/L of ivacaftor (VX-770), for 24 hours. Treatment with ivacaftor increased 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 .
• Cell Research:
  HEK293 cells were seeded on poly-lysine precoated six-well plates at a density of 1.3 x 10^6 cells/well. Six hours after seeding, cells were transiently transfected with 1μg of ABCB4-encoding plasmids using Turbofect, following the manufacturer's instructions. Twenty-four hours post-transfection, cells were washed twice with HBSS, then the medium was replaced by phenol red-free DMEM containing 0.5 mmol/L sodium taurocholate and 0.02% fatty acid–free bovine serum albumin (BSA) in the presence or absence of 10 μmol/L of ivacaftor, 50 μM/L of UDCA, and 10 μmol/L of ivacaftor plus 50 μM/L of UDCA. Media were collected after 24 hours .
• Animal Research:
  Male mouse,Sprague Dawley rats,beagle dog,and cynomolgus monkeys (n = 3/group) were administered a single iv dose of compound formulated in dimethyl isosorbide/ethanol/PEG400/5% dextrose in water (D5W) (10%/15%/35%/40%) at the nominal dose indicated in a dose volume of 1 mL/kg.Blood samples (0.3 mL,sodium heparin anticoagulant) were collected from an indwelling carotid cannula at the following nominal time points: at predose,5,15,30,and 45 min and 1,2,4,6,8,12,24,36,and 48 h following iv administration and at predose,0.25,0.50,1,1.5,2,4,8,12,and 24 h following oral administration.The concentration of compound in the plasma samples was determined with a liquid chromatography/tandem mass spectrometry (LC/MS/MS) method,which had a lowest limit of quantitation (LLOQ) of 1 ng/mL and a linearity range between 1 and 2500 ng/mL .

Storage & Handling

• Storage: Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice/Shipping at ambient temperature.
• Expiration Date: 12 months from date of receipt.
• Disclaimer: For research use only

Alternative Names

inhibit, Ivacaftor, Ivacaftor (VX-770), G551D-CFTR, F508del-CFTR, Inhibitor, Autophagy, Cystic fibrosis transmembrane conductance regulator, CFTR, VX770, VX-770, VX 770

Compound Identifiers

PubChem CID

16220172