Design, synthesis and biological evaluation of novel 7-azaspiro[3.5]nonane derivatives as GPR119 agonists

Bioorg Med Chem. 2018 May 1;26(8):1832-1847. doi: 10.1016/j.bmc.2018.02.032. Epub 2018 Feb 20.

Abstract

The design and synthesis of a novel class of 7-azaspiro[3.5]nonane GPR119 agonists are described. In this series, optimization of the right piperidine N-capping group (R2) and the left aryl group (R3) led to the identification of compound 54g as a potent GPR119 agonist. Compound 54g showed a desirable PK profile in Sprague-Dawley (SD) rats and a favorable glucose lowering effect in diabetic rats.

MeSH terms

  • Alkanes / chemical synthesis
  • Alkanes / chemistry*
  • Alkanes / pharmacokinetics
  • Animals
  • Blood Glucose / analysis
  • Cell Line
  • Diabetes Mellitus, Experimental / drug therapy
  • Diabetes Mellitus, Experimental / pathology
  • Drug Design*
  • Glucose Tolerance Test
  • Half-Life
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / therapeutic use
  • Microsomes, Liver / metabolism
  • Piperidines / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Alkanes
  • Blood Glucose
  • GPR119 protein, human
  • Hypoglycemic Agents
  • Piperidines
  • Receptors, G-Protein-Coupled
  • piperidine
  • nonane