ArticleProceedings of the National Academy of Sciences of the United States of America2020
Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers, 4 of them syntheses that pooled it.
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Who cites it
101 citing papers in PubMed, 4 syntheses or guidelines pooled it, 176 citations in OpenAlex.
- Efficacy and safety of orforglipron 12 mg versus orforglipron 36 mg maintenance dose among patients with obesity with or without diabetes: a systematic review and comprehensive meta-analysis.BMC endocrine disorders · 2026Pooled it
- Efficacy and safety of orforglipron in type 2 diabetes mellitus and obesity: a GRADE-assessed meta-analysis and trial sequential analysis with subgroup evaluations by diabetic status, obesity status, and dose regimens.Acta diabetologica · 2026Pooled it
- Investigation into the efficacy and safety profile of oral small-molecule GLP-1 receptor agonists in type 2 diabetes and obesity: a systematic review and meta-analysis.Frontiers in endocrinology · 2026Pooled it
- The efficacy and safety of danuglipron and orforglipron in patients with type 2 diabetes and obesity: a systematic review and meta-analysis.Frontiers in endocrinology · 2025Pooled it
- Pharmacokinetics and Food Effect of HDM1002, a Novel Oral Small-Molecule GLP-1 Receptor Agonist, in Healthy Chinese Volunteers: A Bioequivalence Study.Diabetes, obesity & metabolism · 2026Trial
- Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials.Diabetes, obesity & metabolism · 2026Trial
- A phase 1 single and multiple ascending dose study of orforglipron in Japanese participants with type 2 diabetes.Journal of diabetes investigation · 2026Trial
- Non-clinical and first-in-human characterization of ECC5004/AZD5004, a novel once-daily, oral small-molecule GLP-1 receptor agonist.Diabetes, obesity & metabolism · 2025Trial
- Cryptotanshinone and 15,16-dihydrotanshinone I fromRSC advances · 2026Article
- Clinical Characterization of Enzyme and Transporter Precipitants to Evaluate Drug-Drug Interactions for Orforglipron, a Small Molecule Glucagon-Like Peptide-1 Receptor Agonist.Clinical pharmacology and therapeutics · 2026Article
- Orforglipron: First Approval.Drugs · 2026Review
- Beyond Simple Mimicry: Next-Generation Geometric Architectures and Future Paradigms in Small-Molecule and Macrocyclic Peptidomimetics.Angewandte Chemie (International ed. in English) · 2026Review
- Patient preferences for pharmacological treatments for obesity: The VOICE study.Obesity pillars · 2026Article
- The evolving landscape of obesity pharmacotherapy.Nature reviews. Drug discovery · 2026Review
- Article
- A Lineup for Next Anti-Obesity Medicines: Beyond Incretin-Based Pharmacotherapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- The expanding role of formulations to enable oral delivery of poorly water-soluble drugs.Nature reviews. Drug discovery · 2026Review
- Estimated Oral Semaglutide Exposure Has Distinct Relationships With Glycaemic Response, Weight Loss and Gastrointestinal Tolerability.Diabetes, obesity & metabolism · 2026Article
- Efficacy and safety of orforglipron in obesity with type 2 diabetes mellitus: a GRADE-assessed meta-analysis of randomized controlled trials.Diabetology & metabolic syndrome · 2026Review
- Discovery of Small-Molecule GLP‑1 Receptor Agonists with Improved Oral Pharmacokinetics Based on Orforglipron.ACS medicinal chemistry letters · 2026Article
41 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.