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

被引：87

作者：

Hadida, Sabine ^{[1
]}

Van Goor, Fredrick ^{[1
]}

Zhou, Jinglan ^{[1
]}

Arumugam, Vijayalaksmi ^{[1
]}

McCartney, Jason ^{[1
]}

Hazlewood, Anna ^{[1
]}

Decker, Caroline ^{[1
]}

Negulescu, Paul ^{[1
]}

Grootenhuis, Peter D. J. ^{[1
]}

机构：

[1] Vertex Pharmaceut Inc, San Diego, CA 92121 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 23期

关键词：

TRANSMEMBRANE CONDUCTANCE REGULATOR; CYSTIC-FIBROSIS; SMALL MOLECULES; DRUG DESIGN; RESCUE; IDENTIFICATION; BIOISOSTERISM; HETEROCYCLES; MECHANISMS; CORRECTORS;

D O I：

10.1021/jm5012808

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：9776 / 9795

页数：20

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