1. Academic Validation
  2. DS-8500a, an Orally Available G Protein-Coupled Receptor 119 Agonist, Upregulates Glucagon-Like Peptide-1 and Enhances Glucose-Dependent Insulin Secretion and Improves Glucose Homeostasis in Type 2 Diabetic Rats

DS-8500a, an Orally Available G Protein-Coupled Receptor 119 Agonist, Upregulates Glucagon-Like Peptide-1 and Enhances Glucose-Dependent Insulin Secretion and Improves Glucose Homeostasis in Type 2 Diabetic Rats

  • J Pharmacol Exp Ther. 2018 Dec;367(3):509-517. doi: 10.1124/jpet.118.250019.
Koji Matsumoto 1 Tomomi Yoshitomi 2 Yoko Ishimoto 2 Naomi Tanaka 2 Kanako Takahashi 2 Akiko Watanabe 2 Katsuyoshi Chiba 2
Affiliations

Affiliations

  • 1 End-Organ Disease Laboratories (K.M., T.Y., Y.I., N.T., K.T.), Drug Metabolism and Pharmacokinetics Research Laboratories (A.W.), and Medicinal Safety Research Laboratories (K.C.), Daiichi Sankyo Company Limited, Tokyo, Japan [email protected].
  • 2 End-Organ Disease Laboratories (K.M., T.Y., Y.I., N.T., K.T.), Drug Metabolism and Pharmacokinetics Research Laboratories (A.W.), and Medicinal Safety Research Laboratories (K.C.), Daiichi Sankyo Company Limited, Tokyo, Japan.
Abstract

G protein-coupled receptor 119 (GPR119) has been shown to be highly expressed in small intestinal L-cells and pancreatic β-cells and mediates intracellular cAMP concentration, glucagon-like peptide (GLP-1) secretion, and glucose-stimulated Insulin secretion (GSIS). This study examined the pharmacological effects of 4-(5-{(1R)-1-[4-(cyclopropylcarbonyl) phenoxy]propyl}-1,2,4-oxadiazol-3-yl)-2-fluoro-N-[(2R)-1-hydroxypropan-2-yl]benzamide (DS-8500a), a novel, orally available, selective GPR119 Agonist. In in vitro studies, DS-8500a increased intracellular cAMP in a concentration-dependent manner in human, rat, and mouse GPR119-expressing Chinese hamster ovary (CHO)-K1 cells, with EC50 values of 51.5, 98.4, and 108.1 nmol/l, respectively. DS-8500a had no effect on intracellular cAMP in pcDNA3.1/CHO-K1 cells. In in vivo studies, DS-8500a augmented plasma GLP-1 concentration in Zucker fatty (ZF) rats, and enhanced GSIS and did not change plasma glucose concentration in fasted Sprague-Dawley (SD) rats. A single dose of DS-8500a showed dose-dependent glucose-lowering effects at oral glucose tolerance test (OGTT) in ZF rats. In a repeat-dosing study, DS-8500a had statistically significant glucose-lowering effects at OGTT performed at the 1st day and after 2 weeks of treatment in neonatal streptozotocin-treated (nSTZ) rats, and the efficacy levels of DS-8500a in each test were greater than those of GSK1292263 or MBX-2982, which had been clinically tested previously as GPR119 agonists. Through pharmacokinetics and pharmacodynamics assessment, the high intrinsic activity of DS-8500a was suggested to be one of the reasons for the greater glucose lowering effect in the nSTZ rats. DS-8500a is a useful compound among GPR119 agonists that can maximize the potential benefit of GPR119 in type 2 diabetes.

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