HM47118A, a novel insulinotropic GPR119 agonist and potential oral antidiabetic agent.

AIMS: The G protein-coupled receptor 119 (GPR119), mainly expressed in the pancreas and gastrointestinal tract, increases the intracellular cyclic AMP accumulation, enhances glucose-dependent insulin secretion from pancreatic β cells, and promotes glucagon-like peptide-1 (GLP-1) production by intestinal L cells. We investigated the activities of a novel GPR119 agonist, HM47118A, in vitro and in vivo.

METHODS: In vitro HM47118A activities were evaluated in several cell lines. Mice, rats, and dogs were administered single intravenous or oral doses of HM47118A to evaluate its pharmacokinetics, while its antidiabetic efficacy was evaluated in Zucker diabetic fatty (ZDF) rats.

RESULTS: The half-maximal effective concentrations of HM47118A were 2.0 and 21.8 nM for the activation of human GPR119 in GPR119-CRE-bla CHO-K1 cells and stimulation of GLP-1 secretion by GLUTag cells, respectively. HM47118A increased insulin secretion by MIN-6 cells and the proliferation of NIT-1 pancreatic β cells. The compound showed favorable pharmacokinetic profiles in all three animal models. Administration of HM47118A but not sitagliptin to ZDF rats for 56 days significantly reduced the blood glucose and glycated hemoglobin (HbA1c) levels, increased postprandial insulin levels, and preserved the pancreatic β cell mass.

CONCLUSIONS: HM47118A showed significant antidiabetic potential and may be an effective oral treatment for diabetes.