Design, synthesis and structure activity relationships of indazole and indole derivatives as potent glucagon receptor antagonists

Bioorg Med Chem Lett. 2019 Aug 1;29(15):1974-1980. doi: 10.1016/j.bmcl.2019.05.036. Epub 2019 May 18.

Abstract

A novel series of indazole/indole derivatives were discovered as glucagon receptor (GCGR) antagonists through scaffold hopping based on two literature leads: MK-0893 and LY-2409021. Further structure-activity relationship (SAR) exploration and optimization led to the discovery of multiple potent GCGR antagonists with excellent pharmacokinetic properties in mice and rats, including low systemic clearance, long elimination half-life, and good oral bioavailability. These potent GCGR antagonists could be used for potential treatment of type II diabetes.

Keywords: Diabetes mellitus; Glucagon; Glucagon receptor antagonist; Indazole; Indole.

MeSH terms

  • Humans
  • Indazoles / chemistry*
  • Molecular Structure
  • Receptors, Glucagon / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Indazoles
  • Receptors, Glucagon