Abstract
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 GTPγS 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.
Highlights
GPR40 is a free fatty acidactivated G protein-coupled receptor that is found on the surface of pancreatic b-cells, gastrointestinal enteroendocrine cells, immune cells and parts of the brain
In vitro characterization of AMG 837 A high throughput screen for GPR40 agonists resulted in the identification of a lead series of b-substituted phenylpropanoic acids that was further optimized to obtain AMG 837
GPR40 agonists have been reported to increase insulin secretion in a glucose- dependent manner, and we found that the activity of AMG 837 was glucose dependent
Summary
GPR40 ( known as FFA1 and FFAR1) is a free fatty acidactivated G protein-coupled receptor that is found on the surface of pancreatic b-cells, gastrointestinal enteroendocrine cells, immune cells and parts of the brain. Long chain saturated and unsaturated fatty acids stimulate GPR40, and evidence points to GPR40 being a mechanistic link to the well-known effects of fatty acids to acutely stimulate insulin and incretin secretion [1,2,3]. The effect of fatty acids on insulin and incretin (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)) secretion is blunted or eliminated in mice lacking GPR40 [4]. GPR40 knockout mice show impaired glucose and arginine induced insulin secretion in vivo [5]. Based on these studies, targeting GPR40 with synthetic agonists may represent a novel pathway in the treatment of type 2 diabetes. Because activity of GPR40 agonists on islet b-cells is glucose dependent, it is believed that GPR40 may offer advantages to commonly used sulfonylurea drugs which act independently of ambient glucose levels, resulting in hypoglycemia in some patients [6]
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