Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

被引：53

作者：

Bass, Jonathan Y. ^{[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
]}

Mills, Wendy Y. ^{[1
]}

Navas, Frank, III ^{[1
]}

Parks, Derek J. ^{[6
]}

Smalley, Terrence L., Jr. ^{[1
]}

Spearing, Paul K. ^{[1
]}

Todd, Dan ^{[7
]}

Williams, Shawn P. ^{[2
]}

Wisely, G. Bruce ^{[6
]}

机构：

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

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

[3] GlaxoSmithKline Inc, Dept Mol Pharmacol, Res Triangle Pk, NC 27709 USA

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

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

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

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

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 04期

关键词：

Farnesoid X receptor; FXR; Nuclear receptor modulator; FXR X-ray co-crystal structure; GW; 4064; GSK8062; Bile acid receptor; NR1H4; GSK2324; BILE-ACID RECEPTOR; HEPATIC STELLATE CELLS; NUCLEAR RECEPTOR; NONALCOHOLIC STEATOHEPATITIS; LIVER FIBROSIS; DEFICIENT MICE; MOUSE MODEL; NULL MICE; HOMEOSTASIS; IDENTIFICATION;

D O I：

10.1016/j.bmcl.2010.12.089

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To improve on the drug properties of GSK8062 1b, a series of heteroaryl bicyclic naphthalene replacements were prepared. The quinoline 1c was an equipotent FXR agonist with improved drug developability parameters relative to 1b. In addition, analog 1c lowered body weight gain and serum glucose in a DIO mouse model of diabetes. (C) 2010 Elsevier Ltd. All rights reserved.

引用

页码：1206 / 1213

页数：8

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