Design, synthesis, and biological activity of novel oxazole-based small molecule allosteric GLP-1R agonists.

Glucagon-like peptide-1 receptor is a key target for type 2 diabetes, but current peptide agonists suffer from low oral bioavailability and poor adherence, highlighting the clinical significance of developing small-molecule modulators. Starting from the lead compound V-0219, a series of novel oxazole-containing small-molecule positive allosteric modulators of GLP-1R were designed and synthesized via a scaffold hopping strategy. Systematic structure-activity relationship studies led to the identification of compound 5b, which exhibited superior GLP-1R potentiating activity (44.8% at 10 μM) compared to the lead. Mechanistic studies demonstrated that 5b enhances GLP-1(7-36)- and GLP-1(9-36)-induced cAMP accumulation, directly binds to and stabilizes the GLP-1R protein, and exerts glucose-lowering effects in a GLP-1R-dependent manner. In oral glucose tolerance tests in hGLP-1R knock-in mice, 5b demonstrated modestly improved glucose-lowering efficacy compared to V-0219. In addition, 5b exhibited lower cytotoxicity, favorable metabolic stability in mouse liver microsomes and plasma, and acceptable oral exposure. Collectively, 5b, as a lead compound for orally available small-molecule GLP-1R modulators, warrants further investigation and holds promise for the treatment of type 2 diabetes and related metabolic disorders.