Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control

被引：58

作者：

Semple, Graeme ^{[1
]}

Ren, Albert ^{[1
]}

Fioravanti, Beatriz ^{[1
]}

Pereira, Guillherme ^{[1
]}

Calderon, Imelda ^{[1
]}

Choi, Karoline ^{[1
]}

Xiong, Yifeng ^{[1
]}

Shin, Young-Jun ^{[1
]}

Gharbaoui, Tawfik ^{[1
]}

Sage, Carleton R. ^{[1
]}

Morgan, Michael ^{[2
]}

Xing, Charles ^{[3
]}

Chu, Zhi-Liang ^{[3
]}

Leonard, James N. ^{[3
]}

Grottick, Andrew J. ^{[3
]}

Al-Shamma, Hussein ^{[3
]}

Liang, Yin ^{[4
]}

Demarest, Keith T. ^{[4
]}

Jones, Robert M. ^{[1
]}

机构：

[1] Arena Pharmaceut, Med Chem, San Diego, CA 92121 USA

[2] Arena Pharmaceut, DMPK, San Diego, CA 92121 USA

[3] Arena Pharmaceut, Discovery Biol, San Diego, CA 92121 USA

[4] Johnson & Johnson Pharmaceut Res & Dev LLC, Spring House, PA 19477 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 10期

关键词：

GPR119; agonists; GPCR; Diabetes; GDIS; GLYCEMIC CONTROL; G-PROTEIN-COUPLED-RECEPTOR-119; OLEOYLETHANOLAMIDE; ACTIVATION; RELEASE;

D O I：

10.1016/j.bmcl.2011.03.007

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series, 3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here, 3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：3134 / 3141

页数：8

共 25 条

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