Conformationally constrained farnesoid X receptor (FXR) agonists: Naphthoic acid-based analogs of GW 4064

被引：144

作者：

Akwabi-Ameyaw, Adwoa ^{[1
]}

Bass, Jonathan Y. ^{[1
]}

Caldwell, Richard D. ^{[1
]}

Caravella, Justin A. ^{[2
]}

Chen, Lihong ^{[3
]}

Creech, Katrina L. ^{[4
]}

Deaton, David N. ^{[1
]}

Jones, Stacey A. ^{[5
]}

Kaldor, Istvan ^{[1
]}

Liu, Yaping ^{[3
]}

Madauss, Kevin P. ^{[2
]}

Marr, Harry B. ^{[6
]}

McFadyen, Robert B. ^{[1
]}

Miller, Aaron B. ^{[2
]}

Navas, Frank, III ^{[1
]}

Parks, Derek J. ^{[7
]}

Spearing, Paul K. ^{[1
]}

Todd, Dan ^{[8
]}

Williams, Shawn P. ^{[2
]}

Wisely, G. Bruce ^{[7
]}

机构：

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

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

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

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

[5] GlaxoSmithKline Inc, Mol Discovery Res, Discovery Technol Grp, Res Triangle Pk, NC 27709 USA

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

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 15期

关键词：

farnesoid X receptor agonist; FXR; nuclear receptor modulator; FXR X-ray co-crystal structure; GW; 4064; GSK8062; naphthoic acid; bile acid receptor; NR1H4;

D O I：

10.1016/j.bmcl.2008.06.073

中图分类号：

R914 [药物化学];

学科分类号：

100701 [药物化学];

摘要：

Starting from the known FXR agonist GW 4064 1a, a series of stilbene replacements were prepared. The 6-substituted 1-naphthoic acid 1b was an equipotent FXR agonist with improved developability parameters relative to 1a. Analog 1b also reduced the severity of cholestasis in the ANIT acute cholestatic rat model. Published by Elsevier Ltd.

引用

页码：4339 / 4343

页数：5

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