Identification of an N-oxide pyridine GW4064 analog as a potent FXR agonist

被引：46

作者：

Feng, Song ^{[1
]}

Yang, Minmin ^{[1
]}

Zhang, Zhenshan ^{[1
]}

Wang, Zhanguo ^{[1
]}

Hong, Di ^{[1
]}

Richter, Hans ^{[2
]}

Benson, Gregory Martin ^{[2
]}

Bleicher, Konrad ^{[2
]}

Grether, Uwe ^{[2
]}

Martin, Rainer E. ^{[2
]}

Plancher, Jean-Marc ^{[2
]}

Kuhn, Bernd ^{[2
]}

Rudolph, Markus Georg ^{[2
]}

Chen, Li ^{[1
]}

机构：

[1] Roche R&D Ctr China Ltd, Shanghai 201203, Peoples R China

[2] F Hoffmann La Roche Ltd, CH-4070 Basel, Switzerland

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2009年 / 19卷 / 09期

关键词：

Farnesoid X receptor (FXR); Agonist; N-Oxide pyridine; Isoxazole; NUCLEAR RECEPTOR FXR; BILE-ACIDS; FEEDBACK-REGULATION; ACTIVATION; BINDING; LIGANDS; MICE;

D O I：

10.1016/j.bmcl.2009.03.008

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

According to the docking studies and the analysis of a co-crystal structure of GW4064 with FXR, a series of 3-aryl heterocyclic isoxazole analogs were designed and synthesized. N-Oxide pyridine analog (7b) was identified as a promising FXR agonist with potent binding affinity and good efficacy, supporting our hypothesis that through an additional hydrogen bond interaction between the pyridine substituent of isoxazole analogs and Tyr373 and Ser336 of FXR, binding affinity and functional activity could be improved. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2595 / 2598

页数：4

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