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):9776-95. doi: 10.1021/jm5012808.
Sabine Hadida  1 ,  Fredrick Van Goor ,  Jinglan Zhou ,  Vijayalaksmi Arumugam ,  Jason McCartney ,  Anna Hazlewood ,  Caroline Decker ,  Paul Negulescu ,  Peter D J Grootenhuis
Affiliations
  • 1. Vertex Pharmaceuticals Incorporated , 11010 Torreyana Road, San Diego, California 92121, United States.
PMID: 25441013 DOI: 10.1021/jm5012808
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.

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