Discovery of cyclic guanidines as potent, orally active, human glucagon receptor antagonists

Bioorg Med Chem Lett. 2011 Dec 1;21(23):7131-6. doi: 10.1016/j.bmcl.2011.09.085. Epub 2011 Sep 29.

Abstract

In the course of the development of an aminobenzimidazole class of human glucagon receptor (hGCGR) antagonists, a novel class of cyclic guanidine hGCGR antagonists was discovered. Rapid N-dealkylation resulted in poor pharmacokinetic profiles for the benchmark compound in this series. A strategy aimed at blocking oxidative dealkylation led to a series of compounds with improved rodent pharmacokinetic profiles. One compound was orally efficacious in a murine glucagon challenge pharmacodynamic model and also significantly lowered glucose levels in a murine diabetes model.

MeSH terms

  • Administration, Oral
  • Animals
  • Blood Glucose / drug effects*
  • Cyclization
  • Diabetes Mellitus, Type 2 / drug therapy
  • Disease Models, Animal
  • Dogs
  • Drug Discovery*
  • Guanidines / chemical synthesis*
  • Guanidines / chemistry
  • Guanidines / pharmacology
  • Humans
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology
  • Inhibitory Concentration 50
  • Molecular Structure
  • Rats
  • Receptors, Glucagon / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • Guanidines
  • Hypoglycemic Agents
  • Receptors, Glucagon