Discovery of potent, orally active benzimidazole glucagon receptor antagonists

The discovery and optimization of potent and selective aminobenzimidazole glucagon receptor antagonists are described. One compound possessing moderate pharmacokinetic properties in multiple preclinical species was orally efficacious at inhibiting glucagon-mediated glucose excursion in transgenic mice expressing the human glucagon receptor, and in rhesus monkeys. The compound also significantly lowered glucose levels in a murine model of diabetes.

Graphical abstractPotent and selective aminobenzimidazole glucagon receptor antagonists are described. Compound 36 was orally efficacious in blocking glucagon-dependent glucose production and in lowering glucose levels in an animal model of diabetes.Figure optionsDownload full-size imageDownload as PowerPoint slide