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Orforglipron: difference between revisions

Diff·revision 4 → 5·05:46, 2 Jan 2025

Difference between revision 4 and revision 5 of Orforglipron. 4 lines changed; the page grew by 548 bytes.

Revision 4 — 11:52, 16 Dec 2024
BalanceBirdie (talk)
add the receptor targets to the lead sentence
2,355 bytes ±0		Revision 5 — 05:46, 2 Jan 2025
DPP4_Dagmar (talk)
expand §Reported clinical findings
2,903 bytes +548
11Small-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.{{r|graaf2016}} Orforglipron binds a pocket near the extracellular face of the transmembrane bundle and stabilises an active conformation without reproducing the peptide's binding mode.{{r|kawai2020}}11Small-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.{{r|graaf2016}} Orforglipron binds a pocket near the extracellular face of the transmembrane bundle and stabilises an active conformation without reproducing the peptide's binding mode.{{r|kawai2020}}
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+13Reported 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.{{r|frias2023orfo}}
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13== Molecular basis ==15== Molecular basis ==
14The 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.{{r|kawai2020}}16The 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.{{r|kawai2020}}
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19{{reflist}}21{{reflist}}
20<ref name="kawai2020">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.</ref>22<ref name="kawai2020">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.</ref>
+23<ref name="frias2023orfo">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.</ref>
21<ref name="graaf2016">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.</ref>24<ref name="graaf2016">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.</ref>
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24[[Category:Small-molecule incretin agonists]]27[[Category:Small-molecule incretin agonists]]
25[[Category:Compounds and pharmacology]]28[[Category:Compounds and pharmacology]]
+29[[Category:Articles describing unapproved compounds]]
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