Discovery, optimisation and in vivo evaluation of novel GPR119 agonists

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7310-6. doi: 10.1016/j.bmcl.2011.10.033. Epub 2011 Oct 18.

Abstract

GPR119 is increasingly seen as an attractive target for the treatment of type II diabetes and other elements of the metabolic syndrome. During a programme aimed at developing agonists of the GPR119 receptor, we identified compounds that were potent with reduced hERG liabilities, that had good pharmacokinetic properties and that displayed excellent glucose-lowering effects in vivo. However, further profiling in a GPR119 knock-out (KO) mouse model revealed that the biological effects were not exclusively due to GPR119 agonism, highlighting the value of transgenic animals in drug discovery programs.

MeSH terms

  • Administration, Oral
  • Animals
  • Diabetes Mellitus, Experimental / drug therapy
  • Drug Evaluation, Preclinical
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Humans
  • Hypoglycemic Agents / chemistry*
  • Hypoglycemic Agents / pharmacokinetics
  • Hypoglycemic Agents / therapeutic use
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / deficiency
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • GPR119 protein, human
  • Gpr119 protein, mouse
  • Hypoglycemic Agents
  • KCNH2 protein, human
  • Receptors, G-Protein-Coupled