Synthesis of 4-(3-biaryl)quinoline sulfones as potent liver X receptor agonists

被引：12

作者：

Ullrich, John W. ^{[1
]}

Morris, Robert ^{[1
]}

Bernotas, Ronald C. ^{[1
]}

Travins, Jeremy M. ^{[1
]}

Jetter, James ^{[1
]}

Unwalla, Rayomand ^{[1
]}

Quinet, Elaine ^{[2
]}

Nambi, Ponnal ^{[2
]}

Feingold, Irene ^{[3
]}

Huselton, Christine ^{[3
]}

Enroth, Christofer ^{[4
]}

Wilhelmsson, Anna ^{[4
]}

Goos-Nilsson, Annika ^{[4
]}

Wrobel, Jay ^{[1
]}

机构：

[1] Wyeth Pharmaceut, Chem Sci, Collegeville, PA 19426 USA

[2] Wyeth Pharmaceut, Cardiovasc & Metab Dis, Collegeville, PA 19426 USA

[3] Wyeth Pharmaceut, Drug Safety & Metab, Collegeville, PA 19426 USA

[4] Novum, Karo Bio AB, S-14157 Huddinge, Sweden

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 09期

关键词：

Liver X receptor; LXR; Quinoline; Sulfone; ABCA1; Atherosclerosis; Lipid; Cholesterol; CROSS-COUPLING REACTION; CHOLESTEROL; ATHEROSCLEROSIS; QUINOLINES; DISEASE; MODULATORS; DISCOVERY; LESSONS; EFFLUX; ABCA1;

D O I：

10.1016/j.bmcl.2010.03.031

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 4-(3-biaryl)quinolines with sulfone substituents on the terminal aryl ring (8) was prepared as potential LXR agonists. High affinity LXR beta ligands with generally modest binding selectivity over LXR alpha and excellent agonist potency in LXR functional assays were identified. Many compounds had LXR beta binding IC(50) values <10 nM while the most potent had EC(50) values <1.0 nM in an ABCA1 mRNA induction assay in J774 mouse cells with efficacy comparable to T0901317. Sulfone 8a was further evaluated in LDL (-/-) mice and shown to reduce atherosclerotic lesion progression. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：2903 / 2907

页数：5

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