Discovery and optimization of N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamides as novel GPR119 agonists

Bioorg Med Chem Lett. 2014 Jan 1;24(1):156-60. doi: 10.1016/j.bmcl.2013.11.053. Epub 2013 Dec 1.

Abstract

The discovery and optimization of novel N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yloxy)phenyl)benzenesulfonamide GPR119 agonists is described. Modification of the pyridylphthalimide motif of the molecule with R(1)=-Me and R(2)=-(i)Pr substituents, incorporated with a 6-fluoro substitution on the central phenyl ring offered a potent and metabolically stable tool compound 22.

Keywords: Agonist; GPR119; Type 2 diabetes.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Microsomes, Liver / chemistry
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Pyridines / chemistry
  • Pyridines / metabolism
  • Pyridines / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Structure-Activity Relationship
  • Sulfonamides / chemistry
  • Sulfonamides / metabolism
  • Sulfonamides / pharmacology*

Substances

  • GPR119 protein, human
  • N-(3-(1,3-dioxo-2,3-dihydro-1H-pyrrolo(3,4-c)pyridin-4-yloxy)phenyl)benzenesulfonamide
  • Pyridines
  • Receptors, G-Protein-Coupled
  • Sulfonamides