Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppressi Show more
Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by intestinal endocrine L cells that activates the GLP-1 receptor (GLP-1R), leading to glucose-dependent insulin secretion and suppression of glucagon release. In recent years, GLP-1R agonists (GLP-1RAs) have become one of the leading therapeutic options for the treatment of type 2 diabetes mellitus; however, for a long time clinically approved GLP-1RAs were limited to peptide drugs unsuitable for oral administration. The discovery of the "first-in-class" small molecule agonist danuglipron in 2018 demonstrated the feasibility of orally available GLP-1RAs and stimulated the development of numerous danuglipron-like compounds, some of which showed increased efficacy over the prototype. In this study, we report the design and synthesis of novel GLP-1RAs based on a regioisomeric danuglipron scaffold, 1 Show less