AMG 837: A Novel GPR40/FFA1 Agonist that Enhances Insulin Secretion and Lowers Glucose Levels in Rodents

被引：68

作者：

Lin, Daniel C. -H. ^{[1
]}

Zhang, Jane ^{[1
]}

Zhuang, Run ^{[1
]}

Li, Frank ^{[1
]}

Kathy Nguyen ^{[1
]}

Chen, Michael ^{[1
]}

Thanhvien Tran ^{[1
]}

Lopez, Edwin ^{[1
]}

Lu, Jenny Ying Lin ^{[1
]}

Li, Xiaoyan Nina ^{[1
]}

Tang, Liang ^{[3
]}

Tonn, George R. ^{[3
]}

Swaminath, Gayathri ^{[1
]}

Reagan, Jeff D. ^{[1
]}

Chen, Jin-Long ^{[1
]}

Tian, Hui ^{[1
]}

Lin, Yi-Jyun ^{[1
]}

Houze, Jonathan B. ^{[2
]}

Luo, Jian ^{[1
]}

机构：

[1] Amgen Inc, Metab Disorders, San Francisco, CA USA

[2] Amgen Inc, Chem Res & Discovery, San Francisco, CA USA

[3] Amgen Inc, Pharmacokinet & Drug Metab, San Francisco, CA USA

来源：

PLOS ONE | 2011年 / 6卷 / 11期

关键词：

PANCREATIC BETA-CELLS; PROTEIN-COUPLED RECEPTORS; FATTY-ACID STIMULATION; OBESE FA/FA RATS; DISCOVERY; GENE; TOLERANCE; RELEASE; POTENT; MICE;

D O I：

10.1371/journal.pone.0027270

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Agonists of GPR40 (FFA1) have been proposed as a means to treat type 2 diabetes. Through lead optimization of a high throughput screening hit, we have identified a novel GPR40 agonist called AMG 837. The objective of these studies was to understand the preclinical pharmacological properties of AMG 837. The activity of AMG 837 on GPR40 was characterized through GTP gamma S binding, inositol phosphate accumulation and Ca2+ flux assays. Activity of AMG 837 on insulin release was assessed on isolated primary mouse islets. To determine the anti-diabetic activity of AMG 837 in vivo, we tested AMG 837 using a glucose tolerance test in normal Sprague-Dawley rats and obese Zucker fatty rats. AMG 837 was a potent partial agonist in the calcium flux assay on the GPR40 receptor and potentiated glucose stimulated insulin secretion in vitro and in vivo. Acute administration of AMG 837 lowered glucose excursions and increased glucose stimulated insulin secretion during glucose tolerance tests in both normal and Zucker fatty rats. The improvement in glucose excursions persisted following daily dosing of AMG 837 for 21-days in Zucker fatty rats. Preclinical studies demonstrated that AMG 837 was a potent GPR40 partial agonist which lowered post-prandial glucose levels. These studies support the potential utility of AMG 837 for the treatment of type 2 diabetes.

引用

页数：10

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