Orforglipron

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]

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.