Discovery of 3-Aryl-4-isoxazolecarboxamides as TGR5 Receptor Agonists

被引：64

作者：

Evans, Karen A. ^{[1
]}

Budzik, Brian W. ^{[1
]}

Ross, Sean A. ^{[4
]}

Wisnoski, David D. ^{[1
]}

Jin, Jian ^{[1
]}

Rivero, Ralph A. ^{[1
]}

Vimal, Mythily ^{[2
]}

Szewczyk, George R. ^{[4
]}

Jayawickreme, Channa ^{[3
]}

Moncol, David L. ^{[3
]}

Rimele, Thomas J. ^{[3
]}

Armour, Susan L. ^{[3
]}

Weaver, Susan P. ^{[3
]}

Griffin, Robert J. ^{[4
]}

Tadepalli, Sarva M. ^{[4
]}

Jeune, Michael R. ^{[4
]}

Shearer, Todd W. ^{[4
]}

Chen, Zibin B. ^{[4
]}

Chen, Lihong ^{[4
]}

Anderson, Donald L. ^{[4
]}

Becherer, J. David ^{[4
]}

De Los Frailes, Maite ^{[5
]}

Javier Colilla, Francisco ^{[5
]}

机构：

[1] GlaxoSmithKline Inc, Discovery Med Chem, Discovery Res, Collegeville, PA 19426 USA

[2] GlaxoSmithKline Inc, Discovery Med Chem, Discovery Res, Harlow CM19 5AD, Essex, England

[3] Discovery Res, Res Triangle Pk, NC 27709 USA

[4] Metab Dis Ctr Excellence Drug Discovery, Res Triangle Pk, NC 27709 USA

[5] GlaxoSmithKline Inc, Dept Screening & Compound Profiling, Discovery Res, Madrid 28760, Spain

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 24期

关键词：

ACID-DERIVATIVES; GLP-1;

D O I：

10.1021/jm901434t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3-aryl-4-isoxazolecarboxamides identified from a high-throughput screening campaign as novel, potent small molecule agonists of the human TGR5 G-protein coupled receptor is described. Subsequent optimization resulted in the rapid identification of potent exemplars 6 and 7 which demonstrated improved GLP-1 secretion in vivo via an intracolonic dose coadministered with glucose challenge in a canine model. These novel TGR5 receptor agonists are potentially useful therapeutics for metabolic disorders such as type II diabetes and its associated complications.

引用

页码：7962 / 7965

页数：4

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