SCO-267, a GPR40 Full Agonist, Improves Glycemic and Body Weight Control in Rat Models of Diabetes and Obesity

J Pharmacol Exp Ther. 2019 Aug;370(2):172-181. doi: 10.1124/jpet.118.255885. Epub 2019 Jun 10.

Abstract

The GPR40/FFA1 receptor is a G-protein-coupled receptor expressed in the pancreatic islets and enteroendocrine cells. Here, we report the pharmacological profiles of (3S)-3-cyclopropyl-3-{2-[(1-{2-[(2,2-dimethylpropyl)(6-methylpyridin-2-yl)carbamoyl]-5-methoxyphenyl}piperidin-4-yl)methoxy]pyridin-4-yl}propanoic acid (SCO-267), a novel full agonist of GPR40. Ca2+ signaling and insulin and glucagon-like peptide-1 (GLP-1) secretion were evaluated in GPR40-expressing CHO, MIN6, and GLUTag cells. Hormone secretions and effects on fasting glucose were tested in rats. Single or repeated dosing effects were evaluated in neonatally streptozotocin-induced diabetic rats (N-STZ-1.5 rats), diet-induced obese (DIO) rats, and GPR40-knockout (Ffar1-/- ) mice. Treatment with SCO-267 activated Gq signaling in both high- and low-FFAR1-expressing CHO cells, stimulated insulin secretion in MIN6 cells, and induced GLP-1 release in GLUTag cells. When administered to normal rats, SCO-267 increased insulin, glucagon, GLP-1, glucose-dependent insulinotropic peptide, and peptide YY (PYY) secretions under nonfasting conditions. These results show the full agonistic property of SCO-267 against GPR40. Hypoglycemia was not induced in SCO-267-treated rats during the fasting condition. In diabetic N-STZ-1.5 rats, SCO-267 was highly effective in improving glucose tolerance in single and 2-week dosing studies. DIO rats treated with SCO-267 for 2 weeks showed elevated plasma GLP-1 and PYY levels, reduced food intake, and decreased body weight. In wild-type mice, SCO-267 induced GLP-1 secretion, food intake inhibition, and body weight reduction; however, these effects were abolished in Ffar1-/- mice, indicating a GPR40-dependent mechanism. In conclusion, SCO-267 stimulated islet and gut hormone secretion, improved glycemic control in diabetic rats, and decreased body weight in obese rats. These data suggest the therapeutic potential of SCO-267 for the treatment of diabetes and obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism*
  • Body Weight / drug effects*
  • CHO Cells
  • Cricetulus
  • Cyclopropanes / pharmacology*
  • Cyclopropanes / therapeutic use
  • Diabetes Mellitus, Experimental / blood*
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / drug therapy*
  • Disease Models, Animal
  • Dogs
  • Eating / drug effects
  • Glucagon-Like Peptide 1 / metabolism
  • Humans
  • Insulin Secretion / drug effects
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • Obesity / complications*
  • Piperidines / pharmacology*
  • Piperidines / therapeutic use
  • Propionates / pharmacology*
  • Propionates / therapeutic use
  • Rats
  • Receptors, G-Protein-Coupled / agonists*

Substances

  • Blood Glucose
  • Cyclopropanes
  • G-protein-coupled receptor 40, rat
  • Piperidines
  • Propionates
  • Receptors, G-Protein-Coupled
  • Glucagon-Like Peptide 1