Optimization of oxadiazole derivatives with a spirocyclic cyclohexane structure as novel GPR119 agonists

Bioorg Med Chem Lett. 2019 Aug 15;29(16):2100-2106. doi: 10.1016/j.bmcl.2019.07.004. Epub 2019 Jul 3.

Abstract

We describe here a novel GPR119 agonist 24, which showed a potent and long-acting hypoglycemic effect in rats via oral dosing. For the discovery of 24, we chose compound 5, which possessed an oxadiazole linker, as a lead compound among our spirocyclic cyclohexane GPR119 agonist series, taking into account its lower plasma protein binding nature. 3,5-Difluoro and 4-methylsulfonylmethy groups on the left side phenyl group, and a gem-difluoro group on the right side of 24 are important for its agonist potency and metabolic stability, respectively.

Keywords: GPR119 agonist; Spirocyclic.

MeSH terms

  • Animals
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / pharmacokinetics
  • Cyclohexanes / pharmacology*
  • Drug Stability
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / pharmacology*
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / pharmacology*
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / pharmacokinetics
  • Spiro Compounds / pharmacology*
  • Structure-Activity Relationship

Substances

  • Cyclohexanes
  • GPR119 protein, human
  • Hypoglycemic Agents
  • Oxadiazoles
  • Receptors, G-Protein-Coupled
  • Spiro Compounds