VX-770 (Ivacaftor) is a potentiator of CFTR, which targeting G551D-CFTR and F508del-CFTR with EC50 of 100 nM and 25 nM, respectively. VX-770 (Ivacaftor) inhibits excessive ENaC-mediated Na+ and fluid absorption with an IC50 of 43 nM, and decreases the amiloride response, resulting in an increase in the surface fluid and cilia beat frequency (CBF) in G551D/F508del HBE. VX-770 (Ivacaftor) is the first potent and orally available CFTR potentiator to enter human clinical trials. It showed that VX-770 (Ivacaftor) was associated with within-subject improvements in CFTR and lung function. These findings provide support for further studies of pharmacologic potentiation of CFTR as a means to treat cystic fibrosis.
|Source||Physiology University of Toronto (2015). Figure 21. VX-770 (AbMole BioScience, Cedarlane, Burlington, Canada)|
|Cell Lines||C57BL/6 WT mice|
|Incubation Time||30 min|
|Results||Since CFTR(inh)-172 results in the inhibition of proper CFTR gating leading to an elevated myogenic vasoconstriction, treatment with potentiator VX-770 might also potentiate CFTR’s capacity to transport S1P and, therefore, compensate for part of the lost CFTR.|
|Preparation method||Iodide Flux Assay—Proteoliposomes were reconstituted in the presence of 75 mM KI. The external iodide was exchanged for 75 mM potassium glutamate by gel filtration chromatography. External iodide concentrations were monitored continuously using an iodide-selective electrode (Lazar Research Laboratories, Los Angeles, CA) interfaced to the Digidata 1320A data acquisi ion system and controlled by Clampex 8 software (Axon Instruments, Sunnyvale, CA), as described previously (17, 18).|
|Solubility (25°C)||DMSO 65 mg/mL|
Powder -20°C 3 years ; 4°C 2 years
In solvent -80°C 6 months ; -20°C 1 month
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
 Eckford PD, et al. J Biol Chem. Cystic fibrosis transmembrane conductance regulator (CFTR) potentiator VX-770 (ivacaftor) opens the defective channel gate of mutant CFTR in a phosphorylation-dependent but ATP-independent manner.
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Posenacaftor (PTI-801) is a cystic fibrosis transmembrane regulator (CFTR) protein modulator that corrects the folding and trafficking of CFTR protein. Posenacaftor is used for the research of cystic fibrosis (CF).
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|CFTR corrector 4
CFTR corrector 4 (Compound 13), an active (R,R)-form enantiomer, is a highly potent and orally active cystic fibrosis transmembrane conductance regulator (CFTR) corrector. CFTR corrector 4 can increase CFTR levels at the cell surface and have the potential for treatment of cystic fibrosis.
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