title: Small molecule drug discovery at the glucagon-like peptide-1 receptor.
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.
authors.affiliation: Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Willard
authors.forename: Ana B
authors.initials: AB
authors.lastname: Bueno
authors.forename: Kyle W
authors.initials: KW
authors.lastname: Sloop
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D055808:Drug Discovery; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008024:Ligands; D018027:Receptors, Glucagon / Q000819:agonists* / Q000378:metabolism
chemical_list: C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008024:Ligands; D018027:Receptors, Glucagon