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

• Published in: Journal of medicinal chemistry Vol. 57; no. 23; pp. 9776 - 9795
• Main Authors: Hadida, Sabine, Van Goor, Fredrick, Zhou, Jinglan, Arumugam, Vijayalaksmi, McCartney, Jason, Hazlewood, Anna, Decker, Caroline, Negulescu, Paul, Grootenhuis, Peter D. J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.12.2014; Amer Chemical Soc
• Subjects: Aminophenols - chemical synthesis; Aminophenols - pharmacokinetics; Aminophenols - pharmacology; Animals; Chemistry, Medicinal; Child; Cystic Fibrosis - drug therapy; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Dogs; Humans; Life Sciences & Biomedicine; Macaca fascicularis; Male; Mice; NIH 3T3 Cells; Pharmacology & Pharmacy; Quinolones - chemical synthesis; Quinolones - pharmacokinetics; Quinolones - pharmacology; Rats, Sprague-Dawley; Science & Technology; Structure-Activity Relationship; TRANSMEMBRANE CONDUCTANCE REGULATOR; RESCUE; SMALL MOLECULES; HETEROCYCLES; DRUG DESIGN; BIOISOSTERISM; MECHANISMS; CORRECTORS; CYSTIC-FIBROSIS; IDENTIFICATION
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5012808

Quinolinone-3-carboxamide 1, a novel CFTR potentiator, was discovered using high-throughput screening in NIH-3T3 cells expressing the F508del-CFTR mutation. Extensive medicinal chemistry and iterative structure–activity relationship (SAR) studies to evaluate potency, selectivity, and pharmacokinetic properties resulted in the identification of N-(2,4-di-tert-butyl-5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (VX-770, 48, ivacaftor), an investigational drug candidate approved by the FDA for the treatment of CF patients 6 years of age and older carrying the G551D mutation.