Journal of medicinal chemistryOct 23, 2026

Oral Small-Molecule Drugs That Activate GLP-1 Receptors: Insights from Clinical Trials and Guidelines for Future Development

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Oct 24, 2026

Abstract

Orforglipron is the first approved oral small-molecule GLP-1 receptor agonist.

Oral, nonpeptidic GLP-1 receptor agonists could enhance dosing convenience and patient acceptance compared to current peptidic therapies.
The development of first-generation oral candidates highlights innovative approaches to overcome the limitations of peptide-only therapies.
Next-generation strategies may include designing small molecules that mimic peptides, targeting multiple pathways, and utilizing receptor cooperativity.
Practical considerations for developing these therapies involve optimizing formulations and assessing safety in preclinical models.

Simplified

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.

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Oral Small-Molecule Drugs That Activate GLP-1 Receptors: Insights from Clinical Trials and Guidelines for Future Development

Abstract

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