Small molecule drug discovery at the glucagon-like peptide-1 receptor

Exp Diabetes Res. 2012;2012:709893. doi: 10.1155/2012/709893. Epub 2012 Feb 23.

Abstract

The therapeutic success of peptide glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes mellitus has inspired discovery efforts aimed at developing orally available small molecule GLP-1 receptor agonists. Although the GLP-1 receptor is a member of the structurally complex class B1 family of GPCRs, in recent years, a diverse array of orthosteric and allosteric nonpeptide ligands has been reported. These compounds include antagonists, agonists, and positive allosteric modulators with intrinsic efficacy. In this paper, a comprehensive review of currently disclosed small molecule GLP-1 receptor ligands is presented. In addition, examples of "ligand bias" and "probe dependency" for the GLP-1 receptor are discussed; these emerging concepts may influence further optimization of known molecules or persuade designs of expanded screening strategies to identify novel chemical starting points for GLP-1 receptor drug discovery.

Publication types

  • Review

MeSH terms

  • Diabetes Mellitus, Type 2 / drug therapy*
  • Drug Discovery*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Ligands
  • Receptors, Glucagon / agonists*
  • Receptors, Glucagon / metabolism

Substances

  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Ligands
  • Receptors, Glucagon