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Experimental Diabetes Research
Volume 2012, Article ID 709893, 9 pages
Review Article

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

1Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
2Centro de Investigación Lilly, Eli Lilly and Company, 28108 Alcobendas, Madrid, Spain
3Endocrine Discovery, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA

Received 31 December 2011; Accepted 24 January 2012

Academic Editor: Matteo Monami

Copyright © 2012 Francis S. Willard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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.