The Design and Synthesis of a Potent Glucagon Receptor Antagonist With Favorable Physicochemical and Pharmacokinetic Properties as a Candidate for the Treatment of Type 2 Diabetes Mellitus

Bioorg Med Chem Lett. 2013 May 15;23(10):3051-8. doi: 10.1016/j.bmcl.2013.03.014. Epub 2013 Mar 13.


A novel and potent small molecule glucagon receptor antagonist for the treatment of diabetes mellitus is reported. This candidate, (S)-3-[4-(1-{3,5-dimethyl-4-[4-(trifluoromethyl)-1H-pyrazol-1-yl]phenoxy}butyl)benzamido]propanoic acid, has lower molecular weight and lipophilicity than historical glucagon receptor antagonists, resulting in excellent selectivity in broad-panel screening, lower cytotoxicity, and excellent overall in vivo safety in early pre-clinical testing. Additionally, it displays low in vivo clearance and excellent oral bioavailability in both rats and dogs. In a rat glucagon challenge model, it was shown to reduce the glucagon-elicited glucose excursion in a dose-dependent manner and at a concentration consistent with its rat in vitro potency. Its properties make it an excellent candidate for further investigation.

MeSH terms

  • Animals
  • Chemistry, Physical
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Epithelial Cells / drug effects
  • Haplorhini
  • Humans
  • Liver / cytology
  • Mice
  • Molecular Structure
  • Propionates / administration & dosage
  • Propionates / chemical synthesis
  • Propionates / pharmacology*
  • Rats
  • Receptors, Glucagon / antagonists & inhibitors*
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Propionates
  • Receptors, Glucagon
  • Small Molecule Libraries