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Updated: May 22, 2026

Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine
Published on: February 26, 2019
Small molecule drug discovery at the glucagon-like peptide-1 receptor
Francis S Willard1, Ana B Bueno, Kyle W Sloop
1Translational Science and Technologies, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
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.
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