title: 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.
abstract: 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.
authors.affiliation: Vertex Pharmaceuticals Incorporated , 11010 Torreyana Road, San Diego, California 92121, United States.
authors.forename: Sabine
authors.initials: S
authors.lastname: Hadida
authors.forename: Fredrick
authors.initials: F
authors.lastname: Van Goor
authors.forename: Jinglan
authors.initials: J
authors.lastname: Zhou
authors.forename: Vijayalaksmi
authors.initials: V
authors.lastname: Arumugam
authors.forename: Jason
authors.initials: J
authors.lastname: McCartney
authors.forename: Anna
authors.initials: A
authors.lastname: Hazlewood
authors.forename: Caroline
authors.initials: C
authors.lastname: Decker
authors.forename: Paul
authors.initials: P
authors.lastname: Negulescu
authors.forename: Peter D J
authors.initials: PD
authors.lastname: Grootenhuis
mesh_terms: D000627:Aminophenols / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D002648:Child; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics* / Q000378:metabolism*; D004285:Dogs; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D015363:Quinolones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000627:Aminophenols; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor