Substituted isoxazole analogs of farnesoid X receptor (FXR) agonist GW4064

被引：52

作者：

Bass, Jonathan Y. ^{[1
]}

Caldwell, Richard D. ^{[1
]}

Caravella, Justin A. ^{[2
]}

Chen, Lihong ^{[3
]}

Creech, Katrina L. ^{[4
]}

Deaton, David N. ^{[1
]}

Madauss, Kevin P. ^{[2
]}

Marr, Harry B. ^{[5
]}

McFadyen, Robert B. ^{[1
]}

Miller, Aaron B. ^{[2
]}

Parks, Derek J. ^{[6
]}

Todd, Dan ^{[7
]}

Williams, Shawn P. ^{[2
]}

Wisely, G. Bruce ^{[6
]}

机构：

[1] GlaxoSmithKline, Dept Med Chem, Res Triangle Pk, NC 27709 USA

[2] GlaxoSmithKline, Computat & Struct Chem Res, Mol Discovery Res, Res Triangle Pk, NC 27709 USA

[3] GlaxoSmithKline, Dept Metab Dis, Res Triangle Pk, NC 27709 USA

[4] GlaxoSmithKline, Mol Discovery Res, Screening & Compound Profiling, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline, Dept Drug Metab & Pharmacokinet, Res Triangle Pk, NC 27709 USA

[6] GlaxoSmithKline, Mol Discovery Res, Biol Reagents & Assay Dev, Res Triangle Pk, NC 27709 USA

[7] GlaxoSmithKline, Dept Pharmaceut Dev Phys Properties & Developabil, Res Triangle Pk, NC 27709 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 11期

关键词：

Farnesoid X receptor agonist; FXR; Nuclear receptor modulator; FXR X-ray co-crystal structure; GW4064; Bile acid receptor; NR1H4; HEPATIC STELLATE CELLS; NUCLEAR RECEPTOR; ACID; IDENTIFICATION; MODELS;

D O I：

10.1016/j.bmcl.2009.04.047

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Starting from the known FXR agonist GW 4064 1a, a series of alternately 3,5-substituted isoxazoles was prepared. Several of these analogs were potent full FXR agonists. A subset of this series, with a tether between the isoxazole ring and the 3-position aryl substituent, were equipotent FXR agonists to GW 4064 1a, with the 2,6-dimethyl phenol analog 1t having greater FRET FXR potency than GW 4064 1a. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2969 / 2973

页数：5

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