Evaluation of novel TGR5 agonist in combination with Sitagliptin for possible treatment of type 2 diabetes

Bioorg Med Chem Lett. 2018 Jun 1;28(10):1849-1852. doi: 10.1016/j.bmcl.2018.04.011. Epub 2018 Apr 5.

Abstract

TGR5 is a member of G protein-coupled receptor (GPCR) superfamily, a promising molecular target for metabolic diseases. Activation of TGR5 promotes secretion of glucagon-like peptide-1 (GLP-1), which activates insulin secretion. A series of 2-thio-imidazole derivatives have been identified as novel, potent and orally efficacious TGR5 agonists. Compound 4d, a novel TGR5 agonist, in combination with Sitagliptin, a DPP-4 inhibitor, has demonstrated an adequate GLP-1 secretion and glucose lowering effect in animal models, suggesting a potential clinical option in treatment of type-2 diabetes.

Keywords: DPP-4 inhibitor; GLP1 secretion; GPBAR1; Sitagliptin; TGR5; TGR5 agonist; Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / veterinary
  • Drug Therapy, Combination
  • Female
  • Glucagon-Like Peptide 1 / metabolism
  • Half-Life
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use
  • Imidazoles / chemistry*
  • Imidazoles / pharmacokinetics
  • Imidazoles / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Molecular Docking Simulation
  • Protein Structure, Tertiary
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Sitagliptin Phosphate / therapeutic use
  • Structure-Activity Relationship

Substances

  • GPBAR1 protein, human
  • Hypoglycemic Agents
  • Imidazoles
  • Receptors, G-Protein-Coupled
  • imidazole
  • Glucagon-Like Peptide 1
  • Sitagliptin Phosphate