# Orforglipron

> Orforglipron is an orally active small-molecule (nonpeptide) agonist of the glucagon-like peptide-1 (GLP-1) receptor. Discovered under the codes LY3502970 and OWL833, it binds a distinct pocket of the receptor and signals with a bias toward G protein activation. It has been tested in phase 3 trials in obesity and type 2 diabetes, and the FDA approved it for weight management in 2026.

Canonical: https://peptideproperties.com/compounds/orforglipron/

## Identity

- **Class:** Incretin & Metabolic Receptor Agonists
- **Also known as:** LY3502970
- **Molecular formula:** C48H48F2N10O5
- **Molecular weight:** 883.0 g/mol
- **Monoisotopic mass:** 882.3777 Da
- **CAS number:** 2212020-52-3
- **PubChem CID:** 137319706
- **InChIKey:** USUWIEBBBWHKNI-KHIFEHGGSA-N

## Key facts

- Class: small-molecule, nonpeptide GLP-1 receptor agonist (partial, G protein-biased)
- Formula C48H48F2N10O5; molecular weight 883.0 g/mol (PubChem CID 137319706)
- CAS Registry Number 2212020-52-3; four defined stereocenters
- Development codes LY3502970 and OWL833
- Binds the human GLP-1 receptor with a reported Ki of about 1 nM
- Phase 3 trials completed in obesity and in early type 2 diabetes
- FDA approved in 2026 for chronic weight management in adults

## What Is Orforglipron?

Orforglipron is a synthetic small molecule that activates the GLP-1 receptor without being a peptide. It was reported in 2020 under the codes LY3502970 and OWL833 as an orally active nonpeptide GLP-1 receptor agonist.[1]Approved GLP-1 receptor agonists before it were peptide based, and the discovery authors noted that small-molecule activators with suitable drug properties had proven difficult to obtain.[1] A 2026 review groups orforglipron with other orally active small-molecule GLP-1 receptor agonists, such as danuglipron, and notes that these molecules resist the enzymatic degradation that affects peptides.[2]Orforglipron has been studied for type 2 diabetes and weight management in a program that runs from phase 1 studies in healthy adults to phase 3 trials.[3][4][5]

## Chemical Structure and Molecular Identity

Orforglipron is a small organic molecule with no amino-acid sequence. PubChem (CID 137319706) lists its molecular formula as C48H48F2N10O5 and its molecular weight as 883.0 g/mol, and its CAS Registry Number is 2212020-52-3.
### Structural features

- Core: an indole bearing a 2,2-dimethyltetrahydropyran ring and linked through an amide to a tetrahydropyrazolo[4,3-c]pyridine system.
- Aromatic substituents: a 4-fluoro-3,5-dimethylphenyl group and a 4-fluoro-1-methylindazole joined through an imidazolone ring, accounting for the two fluorine atoms.
- Acidic group: a 1,2,4-oxadiazol-5-one attached to a methylcyclopropyl ring on the indole nitrogen.
- Stereochemistry: four defined stereocenters, given in the IUPAC name as (1S,2S) on the cyclopropane and (4S) at the tetrahydropyran and pyrazolopyridine positions.PubChem's computed properties include an XLogP of 6.8, a topological polar surface area of 144 Ų, 1 hydrogen-bond donor, 10 hydrogen-bond acceptors and 7 rotatable bonds. Its molecular weight is well above the 500 Da guideline of Lipinski's rule of five, which is notable for an orally active drug candidate. The InChIKey is USUWIEBBBWHKNI-KHIFEHGGSA-N.

## Research History and Development

Orforglipron moved from a 2020 structural and pharmacology report to phase 1 studies published in 2023, a phase 2 obesity trial in 2023, and phase 3 trials published in 2025.
### Discovery
The 2020 discovery paper reported a high-resolution structure of the compound bound to the active-state GLP-1 receptor and efficacy studies in humanized GLP-1 receptor transgenic mice and nonhuman primates.[1]
### Phase 1
A phase 1a study in 92 healthy adults tested single and multiple ascending doses over up to 4 weeks.[3] A phase 1b study in people with type 2 diabetes randomized 68 participants (51 to orforglipron and 17 to placebo) for 12 weeks across several treatment arms.[4]
### Phase 2 and phase 3
A 36-week phase 2 trial randomized 272 adults with obesity, or overweight plus a weight-related condition, and without diabetes to one of four dose levels or placebo.[5] Two phase 3 trials followed: a 40-week trial in 559 adults with early type 2 diabetes managed with diet and exercise, and a 72-week multinational trial in 3,127 adults with obesity without diabetes.[6][7] A 2025 systematic review listed orforglipron among the GLP-1 receptor agonists then in phase 3 obesity trials.[8]

## Mechanisms Studied in Research

Orforglipron is a high-affinity, selective partial agonist of the human GLP-1 receptor that favors G protein signaling over β-arrestin recruitment.[1][9]
### Binding site
In the high-resolution receptor structure, the compound occupies a unique pocket in the upper helical bundle, contacted by the extracellular domain, extracellular loop 2 and transmembrane helices 1, 2, 3 and 7.[1] The authors proposed that this binding mode creates a distinct receptor conformation that may explain the partial agonism and biased signaling. An interaction with the primate-specific tryptophan 33 of the extracellular domain explains why activity is species selective.[1]
### Receptor pharmacology
Competition binding experiments gave an inhibition constant (Ki) of about 1 nM at the human GLP-1 receptor, and signaling assays showed low intrinsic efficacy and negligible β-arrestin recruitment.[9] In mice expressing the human receptor, low receptor occupancy was sufficient to produce a full glucose-lowering response.[9]
### Animal models
Because its activity depends on the primate-specific tryptophan 33, researchers used humanized mice and rats gene-edited to carry a sensitizing receptor variant (Glp1rS33W).[1][9] In these rats, target engagement in the pancreas and brain was consistent with peptide GLP-1 receptor agonists, and oral orforglipron produced weight loss in diet-induced obesity and sustained efficacy started with injected semaglutide.[9] In nonhuman primates, it produced insulinotropic and food-intake-lowering effects comparable to injectable exenatide.[1]

## Key Findings From Published Studies

Phase 2 and phase 3 trials report dose-related reductions in body weight and glycated hemoglobin (HbA1c) with orforglipron compared with placebo, and gastrointestinal events were the most common adverse effects.[5][6][7]StudyPopulation and durationMain result vs placeboPhase 2 obesity[5]272 adults without diabetes; 36 weeksBody weight −9.4% to −14.7% vs −2.3%Phase 3 early type 2 diabetes[6]559 adults; 40 weeksHbA1c −1.24 to −1.48 points vs −0.41Phase 3 obesity[7]3,127 adults without diabetes; 72 weeksBody weight −7.5% to −11.2% vs −2.1%
### Early clinical pharmacology
In healthy adults, exposure was approximately dose proportional and the mean half-life ranged from 24.6 to 35.3 hours after a single dose and from 48.1 to 67.5 hours at day 28. Body weight fell by up to 5.4 kg over 4 weeks versus 2.4 kg with placebo, fasting glucose decreased and gastric emptying was delayed.[3]
### Obesity
In the phase 3 obesity trial, 54.6% of the highest-dose group lost at least 10% of body weight, 36.0% at least 15% and 18.4% at least 20%, compared with 12.9%, 5.9% and 2.8% with placebo.[7] In the earlier phase 2 trial, weight change at the 26-week primary endpoint ranged from −8.6% to −12.6% versus −2.0% with placebo, and 46% to 75% of participants lost at least 10% by week 36, versus 9%.[5] Adverse events led to discontinuation in 5.3% to 10.3% of orforglipron groups versus 2.7% with placebo.[7]
### Type 2 diabetes
In the 40-week phase 3 trial, baseline HbA1c averaged 8.0% and fell to 6.5% to 6.7% with orforglipron; all three dose levels were superior to placebo.[6] In the 12-week phase 1b study, HbA1c changed by −1.5% to −1.8% across orforglipron groups versus −0.4% with placebo.[4]
### Comparative analyses
A 2026 BMJ network meta-analysis estimated one-year weight loss of 9.9% with orforglipron versus lifestyle modification alone, and placed it among the drugs with the highest discontinuation for adverse events.[10] A separate network meta-analysis in adults without diabetes found that orforglipron carried the highest nausea risk among the GLP-1 receptor agonists evaluated.[11]Because orforglipron has four stereocenters, HPLC and mass spectrometry certificates of analysis, ideally with chiral purity data, are the practical identity check.

## Regulatory and Research Status

Orforglipron is FDA approved: in 2026 the US Food and Drug Administration approved it for adults with obesity, or with overweight and weight-related comorbidities.Most of the peer-reviewed literature cited on this page predates that decision and describes orforglipron as investigational or in clinical development for type 2 diabetes and weight management.[6][7] Its phase 3 type 2 diabetes data come from participants managed with diet and exercise alone.[6]Reviewers highlight gastrointestinal tolerability as the main limitation reported across trials, with nausea, vomiting and adverse-event discontinuations more frequent than with placebo.[10][11] Nothing on this page is guidance for human use, and research material outside the approved medicine and registered clinical trials is intended for laboratory studies only.

## FAQ

**Is orforglipron FDA approved?**
Yes. In 2026 the FDA approved orforglipron for adults with obesity, or with overweight and weight-related comorbidities. Most published trials describe it as investigational because they appeared before approval. Its phase 3 obesity trial reported mean weight change of −7.5% to −11.2% at 72 weeks, compared with −2.1% with placebo.

**Is orforglipron a peptide?**
No. Orforglipron is a small molecule, not a peptide. PubChem lists it as C48H48F2N10O5 with a molecular weight of 883.0 g/mol, about one-fifth the mass of lipidated peptide GLP-1 receptor agonists. It contains no amino acids and has no sequence, yet it activates the same receptor that GLP-1 does.

**What is the molecular weight of orforglipron?**
PubChem (CID 137319706) lists orforglipron with a molecular weight of 883.0 g/mol, an exact mass of 882.378, and the molecular formula C48H48F2N10O5. Its CAS Registry Number is 2212020-52-3. The molecule has four defined stereocenters, so its full identity depends on the correct stereoisomer, encoded in its InChIKey.

**How is orforglipron different from semaglutide?**
Semaglutide is a lipidated peptide, while orforglipron is a nonpeptide small molecule. Orforglipron binds a distinct pocket in the upper helical bundle of the GLP-1 receptor and acts as a partial, G protein-biased agonist with negligible β-arrestin recruitment. In gene-edited rats, oral orforglipron sustained weight loss started with semaglutide.

**What is LY3502970?**
LY3502970 is the development code for orforglipron; the 2020 discovery paper in PNAS also lists the code OWL833. That paper described the compound's binding site on the GLP-1 receptor, its partial and biased agonism, and its glucose-lowering and food-intake effects in humanized mice and nonhuman primates.

**What does the research on orforglipron show?**
Phase 2 and phase 3 trials report dose-related weight and HbA1c reductions compared with placebo. In a 72-week phase 3 obesity trial, the highest-dose group lost 11.2% of body weight versus 2.1% with placebo. Gastrointestinal events were the most common adverse effects, and meta-analyses rank its nausea risk as high.

## References

1. 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 of the United States of America 2020. PMID: 33177239
2. Son JW, le Roux CW, Blüher M, et al. Novel GLP-1-based Medications for Type 2 Diabetes and Obesity. Endocrine reviews 2026. PMID: 41054801
3. Pratt E, Ma X, Liu R, et al. Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants. Diabetes, obesity & metabolism 2023. PMID: 37344954
4. Pratt E, Ma X, Liu R, et al. Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes. Diabetes, obesity & metabolism 2023. PMID: 37264711
5. Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. The New England journal of medicine 2023. PMID: 37351564
6. Rosenstock J, Hsia S, Nevarez Ruiz L, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes. The New England journal of medicine 2025. PMID: 40544435
7. Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. The New England journal of medicine 2025. PMID: 40960239
8. Kokkorakis M, Chakhtoura M, Rhayem C, et al. Emerging pharmacotherapies for obesity: A systematic review. Pharmacological reviews 2025. PMID: 39952695
9. Sloop KW, Cox AL, Wainscott DB, et al. The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron. Science translational medicine 2024. PMID: 39693407
10. Nong K, Shi Q, Xie X, et al. Comparative effects of drugs for adults with overweight or obesity: systematic review and network meta-analysis. BMJ (Clinical research ed.) 2026. PMID: 42419792
11. Ismaiel A, Scarlata GGM, Boitos I, et al. Gastrointestinal adverse events associated with GLP-1 RA in non-diabetic patients with overweight or obesity: a systematic review and network meta-analysis. International journal of obesity (2005) 2025. PMID: 40804463