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. Epub 2014 Dec 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminophenols / chemical synthesis*
  • Aminophenols / pharmacokinetics
  • Aminophenols / pharmacology
  • Animals
  • Child
  • Cystic Fibrosis / drug therapy*
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics*
  • Cystic Fibrosis Transmembrane Conductance Regulator / metabolism*
  • Dogs
  • Humans
  • Macaca fascicularis
  • Male
  • Mice
  • NIH 3T3 Cells
  • Quinolones / chemical synthesis*
  • Quinolones / pharmacokinetics
  • Quinolones / pharmacology
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Aminophenols
  • Quinolones
  • Cystic Fibrosis Transmembrane Conductance Regulator
  • ivacaftor