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.

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