An example of designed multiple ligands spanning protein classes: dual MCH-1R antagonists/DPPIV inhibitors

Bioorg Med Chem Lett. 2012 Apr 1;22(7):2464-9. doi: 10.1016/j.bmcl.2012.02.010. Epub 2012 Feb 13.

Abstract

A ligand-based approach to identify potential starting points for a dual MCH-1R antagonist/DPPIV inhibitor medicinal chemistry program was undertaken. Potential ligand pairs were identified by analysis of MCH-1R and DPPIV in vitro data. A highly targeted synthetic effort lead to the discovery of pyridone 11, a dual MCH-1R antagonist/DPPIV inhibitor with selectivity over DPP8 and DPP9.

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis*
  • Anti-Obesity Agents / pharmacology
  • CHO Cells
  • Cricetinae
  • Dipeptidases / antagonists & inhibitors
  • Dipeptidases / metabolism
  • Dipeptidyl Peptidase 4 / metabolism
  • Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
  • Dipeptidyl-Peptidase IV Inhibitors / pharmacology
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
  • Drug Design
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacology
  • Ligands
  • Pyridones / chemical synthesis*
  • Pyridones / pharmacology
  • Receptors, Somatostatin / antagonists & inhibitors*
  • Receptors, Somatostatin / metabolism

Substances

  • Anti-Obesity Agents
  • Dipeptidyl-Peptidase IV Inhibitors
  • Hypoglycemic Agents
  • Ligands
  • MCHR1 protein, human
  • Pyridones
  • Receptors, Somatostatin
  • Dipeptidases
  • DPP9 protein, human
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • DPP4 protein, human
  • DPP8 protein, human
  • Dipeptidyl Peptidase 4