Orforglipron (revision 9)
Old revision·10:32, 5 Mar 2025·MassSpecMarv
| OrforglipronInvestigational | |
|---|---|
| Development code | LY3502970 |
| Class | Small-molecule GLP-1 receptor agonist |
| Route | Oral, once daily |
| Status | Phase 3; not approved |
| Contrast with oral peptide | |
| Bioavailability | Not limited by proteolysis |
| Food restriction | None required |
| Compare | Oral semaglutide, ≈0.4–1% with fasting conditions |
| Compound infobox · conventions | |
Orforglipron (development code LY3502970) is an investigational orally administered non-peptide agonist of the GLP-1 receptor. It is not a peptide and is not subject to proteolysis, so it requires neither an absorption enhancer nor the strict fasting conditions that govern oral semaglutide.[1]
Small-molecule agonism at a class B G-protein-coupled receptor was long considered difficult, because the natural ligand engages a large surface across two receptor domains.[2] Orforglipron binds a pocket near the extracellular face of the transmembrane bundle and stabilises an active conformation without reproducing the peptide's binding mode.[1]
Reported phase 2 results include glycated-haemoglobin reductions of up to about 2.1 percentage points in type 2 diabetes and weight reduction of up to about 14.7% at 36 weeks in obesity without diabetes. It is not approved in any jurisdiction.[3]
Molecular basis
[edit]The receptor's orthosteric peptide site is a poor target for a small molecule: the natural ligand contacts both the extracellular domain and the transmembrane bundle across a large interface, and a molecule of a few hundred daltons cannot reproduce that. Orforglipron instead occupies a pocket accessible from the extracellular face of the bundle and acts as an agonist by stabilising the same active receptor conformation by a different route.[1]
A consequence is species selectivity. The pocket differs between human and rodent receptors sufficiently that activity does not translate, and preclinical work required humanised receptor models — a practical complication of small-molecule work at this target that peptide agonists do not face.
Signalling profile differs from that of the peptide agonists, with a reported preference for cAMP accumulation over β-arrestin recruitment. Whether that difference has clinical consequences is unknown; see Receptor bias.[1]
Reported clinical findings
[edit]| Trial setting | Duration | Reported result |
|---|---|---|
| Type 2 diabetes, phase 2 | 26 weeks | HbA1c −2.1 percentage points at highest dose |
| Obesity without diabetes, phase 2 | 36 weeks | −14.7% weight at highest dose vs −2.3% placebo |
Gastrointestinal adverse events were dose-related and qualitatively similar to those of injected agonists, which argues that they are a receptor-level rather than a route-level phenomenon.[3][4]
References
- ^ a b c d Kawai T, Sun B, Yoshino H, et al. "Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist." Proceedings of the National Academy of Sciences 117(47):29959–29967 (2020). DOI:10.1073/pnas.2014879117. PMID 33177239.
- ^ de Graaf C, Donnelly D, Wootten D, et al. "Glucagon-like peptide-1 and its class B G protein-coupled receptors." Pharmacological Reviews 68(4):954–1013 (2016). PMID 27630114.
- ^ a b Frías JP, Hsia S, Eyde S, et al. "Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a phase 2 randomised trial." The Lancet 402(10400):472–483 (2023). PMID 37369232.
- ^ Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). PMID 29617641.