Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series

Bioorg Med Chem Lett. 2015 Aug 1;25(15):3034-8. doi: 10.1016/j.bmcl.2015.04.102. Epub 2015 May 23.

Abstract

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.

Keywords: GDIR; GPR119 agonist; T2DM; Trans-1,4-dioxycyclohexane.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / analysis
  • Cyclohexanes / administration & dosage
  • Cyclohexanes / chemistry*
  • Cyclohexanes / pharmacokinetics
  • Cyclohexanes / therapeutic use*
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use*
  • Male
  • Mice
  • Rats, Sprague-Dawley
  • Rats, Zucker
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • Cyclohexanes
  • GPR119 protein, human
  • Hypoglycemic Agents
  • Receptors, G-Protein-Coupled