Phenylalanine derivatives as GPR142 agonists for the treatment of type II diabetes

Bioorg Med Chem Lett. 2012 Oct 1;22(19):6218-23. doi: 10.1016/j.bmcl.2012.08.015. Epub 2012 Aug 10.

Abstract

GPR142 is a novel GPCR that is predominantly expressed in pancreatic β-cells. GPR142 agonists potentiate glucose-dependent insulin secretion, and therefore can reduce the risk of hypoglycemia. Optimization of our lead pyridinone-phenylalanine series led to a proof-of-concept compound 22, which showed in vivo efficacy in mice with dose-dependent increase in insulin secretion and a decrease in glucose levels.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dose-Response Relationship, Drug
  • Drug Stability
  • Glucose Tolerance Test
  • HEK293 Cells
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Insulin / blood
  • Insulin / metabolism
  • Insulin Secretion
  • Male
  • Mice
  • Mice, Inbred Strains
  • Microsomes / chemistry
  • Phenylalanine / administration & dosage
  • Phenylalanine / chemistry
  • Phenylalanine / pharmacology*
  • Rats
  • Receptors, G-Protein-Coupled / agonists*
  • Receptors, G-Protein-Coupled / metabolism
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • GPR142 protein, human
  • GPR142 protein, mouse
  • Hypoglycemic Agents
  • Insulin
  • Receptors, G-Protein-Coupled
  • Phenylalanine