Discovery of furan-2-carbohydrazides as orally active glucagon receptor antagonists

Bioorg Med Chem Lett. 2014 Sep 1;24(17):4266-70. doi: 10.1016/j.bmcl.2014.07.025. Epub 2014 Jul 24.

Abstract

Furan-2-carbohydrazides were found as orally active glucagon receptor antagonists. Starting from the hit compound 5, we successfully determined the structure activity relationships of a series of derivatives obtained by modifying the acidity of the phenol. We identified the ortho-nitrophenol as a good scaffold for glucagon receptor inhibitory activity. Our efforts have led to the discovery of compound 7l as a potent glucagon receptor antagonist with good bioavailability and satisfactory long half-life.

Keywords: Furan-2-carbohydrazide; Glucagon; Glucagon receptor antagonist; Hyperglucagonemia; Type 2 diabetes.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzamides / administration & dosage*
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Hydrazines / administration & dosage*
  • Hydrazines / chemistry
  • Hydrazines / pharmacology*
  • Molecular Structure
  • Rats
  • Receptors, Glucagon / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Benzamides
  • Hydrazines
  • Receptors, Glucagon