1413431-22-7

Ivacaftor-d₁₉ is intended for use as an internal standard for the quantification of ivacaftor by GC- or LC-MS. Ivacaftor is an orally bioavailable potentiator of the cystic fibrosis transmembrane conductance regulator (CFTR) that improves chloride transport. It increases the forskolin-induced CFTR-mediated epithelial current in cells expressing the G551D missense mutation associated with severe cystic fibrosis by approximately 4-fold (EC₅₀ = 100 nM) but has no effect on current in the absence of forskolin. Ivacaftor increases chloride secretion in cultured human cystic fibrosis bronchial epithelial cells carrying the G551D mutation on one allele and the common ΔF508 processing mutation on the other allele. It binds CFTR directly and leads to CFTR channel opening via an ATP-independent mechanism. Formulations containing ivacaftor have been used in the treatment of cystic fibrosis in patients carrying one or more mutations in the CFTR gene.

Ivacaftor-d9 is a potent CFTR modulator and exhibits an EC50 value of 255 nM for CFTR potentiation in G551D/F508del HBE Cells. Ivacaftor-D9 acts as an orally active and improved deuterated Ivacaftor analog for cystic fibrosis research[1].

[1] Russak EM, et al. Impact of Deuterium Substitution on the Pharmacokinetics of Pharmaceuticals. Ann Pharmacother. 2019;53(2):211-216. DOI:10.1177/1060028018797110
[2] 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 DOI:10.1002/hep.28929
[3] 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 DOI:10.1016/j.jcf.2016.09.005
[4] 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 DOI:10.1021/jm5012808
[5] 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. DOI:10.1073/pnas.0904709106