G-protein coupled receptor 119 (GPR119) has emerged as a promising new target for the treatment of type 2 diabetes mellitus. The expression of GPR119 on the pancreatic B cells and intestinal L cells provides a unique opportunity for a single drug to promote insulin and GLP-1 secretion. In this study, we identified a novel small molecule GPR119 agonist, HD0471953, from our large library of synthetic compounds based on its ability to anti-hyperglycemic effects on T2DM murine models. We have tested the acute efficacy of HD0471953 by the oral glucose tolerance test (OGTT) with normal C57BL/6J mice. Then, chronic administrations of HD0471953 were performed to evaluate the efficacy on various diabetic rodent models. Single administration of HD0471953 showed improved glycemic control with a dose-dependent manner in OGTT with normal mice, and the insulin and GLP-1 were also increased. To identify chronic efficacy, we have observed a decline of blood glucose and fasting insulin in a dose-dependent manner of 10, 20, and 50？mpk in db/db mice. The results suggest that HD0471953 may be a potentially promising anti-hyperglycemic agent for the treatment of patients with type 2 diabetes mellitus. 1. Introduction Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia as a result of defects in insulin sensitivity [1, 2]. In patients with T2DM, depletion of glucose-stimulated insulin secretion (GSIS) is a representative feature and leads to postprandial hyperglycemia, especially in the early phase, [3]. In clinical therapy for T2DM, hypoglycemic agents such as metformin, a-glycosidase inhibitors, thiazolidines (TZDs), and sulfonylurea derivatives (SUs) used available. However, these compounds have side effects including hypoglycemia, weight-gain, and cardiovascular problems [4]. GPR119 agonist is currently receiving significant attention for its therapeutic potential as an antidiabetic agent and an appropriate treatment modality for the safe amelioration of metabolic diseases. Activation of GPR119 increases glucagon-like peptide-1 (GLP-1). GLP-1 analogs increase glucose-dependent insulin secretion through the gastrointestinal mechanism, which GLP-1 release in pancreatic b cell and enteroendocrine L cell activated GPR119 [5]. Mimicking these ligands induces GLP-1 secretion and glucose tolerance in normal and diabetic mice [6]. Numerous GPR 119 agonists orally administered have been developed to date [7]. Here, we report the in vivo characterization of the novel small molecule GPR119 agonist HD0471953 that had synthesized in Hyundai Pharm. We specifically
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