Oral Small-Molecule GLP-1 Receptor Agonists: Lessons from Clinical Candidates and a Blueprint for Next-Generation Design

Abstract Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the treatment of type 2 diabetes (T2D) and obesity, yet all approved therapies to date are peptidic, limiting dosing convenience and patient acceptance. The recent clinical advancement of oral, nonpeptidic GLP-1 RAs, including danuglipron, lotiglipron, DA-302168S, and orforglipron, the first approved oral small-molecule GLP-1 RA, demonstrates that the peptide-only barrier can be overcome. Here, we examine these first-generation oral candidates as case studies, highlighting how each achieved novel solutions while revealing remaining design challenges. Building on these insights, we outline next-generation strategies, including peptidomimetic design, design of multi-target agonists, and harnessing of orthosteric and allosteric cooperativity. We also discuss practical considerations for screening cascades, selection of preclinical species and models, formulation optimization and prospective safety assessment. Collectively, these insights provide a conceptual framework for the rational design of oral small-molecule GLP-1RAs, with broader implications for developing therapies challenging G protein-coupled receptor (GPCR) targets.