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Study · Animal study (in vivo) · mouse and nonhuman primate · 2020

9 results

Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist.

Kawai T, Sun B, Yoshino H, Feng D, Suzuki Y, Fukazawa M, Nagao S, Wainscott DB, Showalter AD, Droz BA, Kobilka TS, Coghlan MP and 4 more

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Willard FS, Kawabe Y, Kobilka BK, Sloop KW

Proceedings of the National Academy of Sciences of the United States of America11 Nov 2020Cited by 181 (Europe PMC)

PMID33177239 (opens in a new tab)PMCIDPMC7703558 (opens in a new tab)DOI10.1073/pnas.2014879117 (opens in a new tab)PepBankPUB-33177239
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Summary

Glucagon-like peptide-1 receptor (GLP-1R) agonists are efficacious antidiabetic medications that work by enhancing glucose-dependent insulin secretion and improving energy balance. Currently approved GLP-1R agonists are peptide based, and it has proven difficult to obtain small-molecule activators possessing optimal pharmaceutical properties. We report the discovery and mechanism of action of LY3502970 (OWL833), a nonpeptide GLP-1R agonist. LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R. The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration. A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7. This mechanism creates a distinct receptor conformation that may explain the partial agonism and biased signaling of the compound. Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule. In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide. Together, this work determined the molecular basis for the activity of an oral agent being developed for the treatment of type 2 diabetes mellitus, offering insights into the activation of class B GPCRs by nonpeptide ligands.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study9

7 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In humanized GLP-1R transgenic mice, oral LY3502970 lowered glucose with an effect size comparable to injectable exenatide.

    In plain wordsIn mice with humanized GLP-1R, oral orforglipron lowered glucose with an effect comparable to injected exenatide.

    Peptide
    Orforglipron
    Outcome
    DecreaseGlucose lowering
    Study

    mousen: not reported in source

    Humanized GLP-1R transgenic mice
    Comparator
    Injectable exenatide
    Outcome group
    Glycemic control · Metabolic and weight
    Studied dose
    Dose not stated · oralAs given in this study (mouse).

    Source sentences

    Summary
    In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide.
  2. 02AnimalAnimal study (in vivo)Efficacy outcome

    In nonhuman primates, oral LY3502970 produced insulinotropic effects comparable in size to injectable exenatide.

    In plain wordsIn nonhuman primates, oral orforglipron stimulated insulin with an effect comparable to injected exenatide.

    Peptide
    Orforglipron
    Outcome
    IncreaseInsulinotropic effect
    Study

    nonhuman primaten: not reported in source

    Comparator
    Injectable exenatide
    Outcome group
    Glycemic control · Metabolic and weight
    Studied dose
    Dose not stated · oralAs given in this study (nonhuman primate).

    Source sentences

    Summary
    In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide.
  3. 03AnimalAnimal study (in vivo)Efficacy outcome

    In nonhuman primates, oral LY3502970 produced hypophagic effects comparable in size to injectable exenatide.

    In plain wordsIn nonhuman primates, oral orforglipron reduced food intake with an effect comparable to injected exenatide.

    Peptide
    Orforglipron
    Outcome
    DecreaseHypophagic effect
    Study

    nonhuman primaten: not reported in source

    Comparator
    Injectable exenatide
    Outcome group
    Appetite and food intake · Metabolic and weight
    Studied dose
    Dose not stated · oralAs given in this study (nonhuman primate).

    Source sentences

    Summary
    In efficacy studies, oral administration of LY3502970 resulted in glucose lowering in humanized GLP-1R transgenic mice and insulinotropic and hypophagic effects in nonhuman primates, demonstrating an effect size in both models comparable to injectable exenatide.
  4. 04LabIn vitro (cells)Mechanism

    In receptor experiments, LY3502970 was a partial GLP-1R agonist biased toward G protein activation over beta-arrestin recruitment.

    In plain wordsIn lab tests, orforglipron partly activated GLP-1R and favored G protein activation over beta-arrestin recruitment.

    Peptide
    Orforglipron
    Outcome
    Not applicablePartial agonism and signaling bias
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    LY3502970 is a partial agonist, biased toward G protein activation over β-arrestin recruitment at the GLP-1R.
  5. 05LabIn vitro (cells)Activity measurement

    In receptor experiments, LY3502970 showed high potency.

    In plain wordsIn lab tests, orforglipron showed high potency.

    Peptide
    Orforglipron
    Outcome
    Not applicablePotency
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration.
  6. 06LabIn vitro (cells)Activity measurement

    In receptor experiments, LY3502970 was selective against other class B G protein-coupled receptors.

    In plain wordsIn lab tests, orforglipron showed selectivity against other class B receptors.

    Peptide
    Orforglipron
    Outcome
    Not applicableReceptor selectivity
    Study

    n: not reported in source

    Comparator
    Other class B GPCRs
    Outcome group
    Receptor activity and mechanism · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration.
  7. 07LabOther designPharmacokinetics

    LY3502970 showed a pharmacokinetic profile favorable for oral administration, without a model specified in the abstract.

    In plain wordsIn lab tests, orforglipron showed a drug-exposure profile favorable for oral dosing, but the abstract did not specify the model.

    Peptide
    Orforglipron
    Outcome
    Not applicableOral pharmacokinetic profile
    Study

    n: not reported in source

    Outcome group
    Pharmacokinetics · Pharmacology
    Studied dose
    Dose not stated

    Source sentences

    Summary
    The molecule is highly potent and selective against other class B G protein-coupled receptors (GPCRs) with a pharmacokinetic profile favorable for oral administration.

Studies that did not test the peptide alone2

In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Orforglipron.

  1. 08LabNot a test of Orforglipron aloneIn vitro (cell-free)Mechanism

    In a receptor structure, LY3502970 occupied an upper helical bundle pocket involving the extracellular domain, extracellular loop and transmembrane helices.

    In plain wordsIn lab tests, orforglipron occupied a distinct pocket in the GLP-1 receptor.

    Peptide
    Orforglipron
    Outcome
    Not applicableGLP-1R binding pocket
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    A high-resolution structure of LY3502970 in complex with active-state GLP-1R revealed a unique binding pocket in the upper helical bundle where the compound is bound by the extracellular domain (ECD), extracellular loop 2, and transmembrane helices 1, 2, 3, and 7.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

  2. 09LabNot a test of Orforglipron aloneIn vitro (cell-free)Mechanism

    In receptor analysis, LY3502970 interaction with primate-specific Trp33 informed species selective activity.

    In plain wordsIn lab tests, orforglipron interaction with a primate-specific receptor residue informed species selective activity.

    Peptide
    Orforglipron
    Outcome
    Not applicableSpecies selective activity
    Study

    n: not reported in source

    Outcome group
    Receptor activity and mechanism · Pharmacology

    Source sentences

    Summary
    Further, interaction between LY3502970 and the primate-specific Trp33 of the ECD informs species selective activity for the molecule.

    In this study, Orforglipron was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Orforglipron.

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 1

    14 Oct 2026, 01:46 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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