Discovery and development of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists for the treatment of diabetes

Bioorg Med Chem Lett. 2016 Jun 15;26(12):2947-2951. doi: 10.1016/j.bmcl.2016.04.018.

Abstract

A novel series of benzo-[1,2,4]-triazolo-[1,4]-oxazepine GPR142 agonists are described. The series was designed to address the suboptimal PK (pharmacokinetic) and off-target profile of a class of N-aryl-benzo-[1,4]-oxazepine-4-carboxamides, represented by 1, that were identified from a high-throughput screen of the Merck compound collection for GPR142 agonists. This work led to the discovery of 3-phenoxy-benzo-[1,2,4]-triazolo-[1,4]-oxazepine 47, a potent GPR142 agonist with an off-target and PK profile suitable for in vivo studies. This compound and a related analogue 40 were shown to be active in mouse oral glucose tolerance tests (OGTTs). Furthermore, a GPR142 knock-out mouse OGTT study with compound 40 provides evidence that its glucose-lowering effect is mediated by GPR142.

Keywords: Diabetes; GPR142; Wild-type knock-out study.

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Glucose Tolerance Test
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Oxazepines / chemical synthesis
  • Oxazepines / chemistry
  • Oxazepines / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / deficiency
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*

Substances

  • GPR142 protein, human
  • GPR142 protein, mouse
  • Oxazepines
  • Receptors, G-Protein-Coupled
  • Triazoles
  • benzo-(1,2,4)-triazolo-(1,4)-oxazepine