Small Molecule Drug Discovery at the Glucagon-Like Peptide-1 Receptor

Abstract EN

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.