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 | Health & Environmental Research Online (HERO)

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Citation
Tags

HERO ID

8350901

Reference Type

Journal Article

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

Author(s)

Hadida, S; Van Goor, F; Zhou, J; Arumugam, V; Mccartney, J; Hazlewood, A; Decker, C; Negulescu, P; Grootenhuis, PDJ

Year

2014

Is Peer Reviewed?

Yes

Journal

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804

Volume

Issue

Page Numbers

9776-9795

Language

English

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. © 2014 American Chemical Society.