Synthesis and pharmacological validation of a novel series of non-steroidal FXR agonists

被引：44

作者：

Abel, Ulrich ^{[1
]}

Schlueter, Thomas ^{[1
]}

Schulz, Andreas ^{[1
]}

Hambruch, Eva ^{[1
]}

Steeneck, Christoph ^{[1
]}

Hornberger, Martin ^{[1
]}

Hoffmann, Thomas ^{[1
]}

Perovic-Ottstadt, Sanja ^{[1
]}

Kinzel, Olaf ^{[1
]}

Burnet, Michael ^{[2
]}

Deuschle, Ulrich ^{[1
]}

Kremoser, Claus ^{[1
]}

机构：

[1] Phenex Pharmaceut AG, D-69123 Heidelberg, Germany

[2] Synovo GmbH, D-72076 Tubingen, Germany

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2010年 / 20卷 / 16期

关键词：

Farnesoid X receptor; FXR agonist; GW4064; db/db mice; Metabolic syndrome; FARNESOID-X-RECEPTOR; ORPHAN NUCLEAR RECEPTOR; BILE-ACIDS; IDENTIFICATION; HOMEOSTASIS; MICE;

D O I：

10.1016/j.bmcl.2010.06.084

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

To overcome the known liabilities of GW4064 a series of analogs were synthesized where the stilbene double bond is replaced by an oxymethylene or amino-methylene linker connecting a terminal benzoic acid with a substituted heteroaryl in the middle ring position. As a result we discovered compounds with increased potency in vitro that cause dose-dependent reduction of plasma triglycerides and cholesterol in db/db mice down to 2 x 1 mg/kg/day upon oral administration. (c) 2010 Elsevier Ltd. All rights reserved.

引用

页码：4911 / 4917

页数：7

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