Orforglipron
[CAS# 2212020-52-3]

Identification

• Classification: API >> Inhibitor drug
• Name: Orforglipron
• Synonyms: 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
• Molecular Formula: C₄₈H₄₈F₂N₁₀O₅
• Molecular Weight: 882.96
• CAS Registry Number: 2212020-52-3
• EC Number: 960-735-6
• SMILES: C[C@H]1C[C@]1(C2=NOC(=O)N2)N3C4=C(C=C(C=C4)[C@H]5CCOC(C5)(C)C)C=C3C(=O)N6CCC7=NN(C(=C7[C@@H]6C)N8C=CN(C8=O)C9=C(C1=C(C=C9)N(N=C1)C)F)C1=CC(=C(C(=C1)C)F)C

Properties

• Density: 1.5±0.1 g/cm³, Calc.^*
• Index of Refraction: 1.738, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: 302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

Orforglipron is a novel non-peptide agonist of the glucagon-like peptide-1 receptor (GLP-1R) that represents a major advance in the treatment of metabolic disorders, particularly type 2 diabetes and obesity. This synthetic compound has attracted much attention for its unique properties and potential to provide an oral alternative to existing GLP-1 therapies.

The discovery of Orforglipron stems from an intensive search for effective oral medications to treat type 2 diabetes and obesity. Traditional GLP-1R agonists, such as exenatide and liraglutide, are peptide drugs that require subcutaneous administration, which can be a barrier to patient compliance. The researchers aimed to develop a non-peptide molecule that could mimic the beneficial effects of GLP-1R activation while being suitable for oral administration.

Orforglipron (chemical structure: C26H28FN5O3S) was identified through high-throughput screening and optimization of a small molecule library. Its molecular design enables it to effectively bind to the GLP-1 receptor, mimicking the activity of the natural hormone. Orforglipron is characterized by its stability, oral bioavailability, and potent agonist effect at the GLP-1 receptor.

Orforglipron works by activating the GLP-1 receptor, a key regulator of glucose homeostasis and appetite. Activation of the GLP-1R results in multiple beneficial effects: It stimulates insulin secretion from pancreatic beta cells in a glucose-dependent manner, helping to lower postprandial blood glucose levels. It inhibits the secretion of glucagon, a hormone that increases blood glucose levels, thereby contributing to an overall reduction in hyperglycemia. Orforglipron slows gastric emptying, helping to control appetite and promote satiety, thereby aiding weight loss. It also promotes the health and function of pancreatic beta cells, thereby potentially slowing the progression of type 2 diabetes.

Orforglipron has shown promising results in clinical trials for the management of type 2 diabetes. Its ability to improve glycemic control through multiple mechanisms makes it a valuable addition to diabetes therapy, potentially reducing reliance on insulin and injected GLP-1 agonists.

The appetite suppressant effects of orforglipron are particularly beneficial in the treatment of obesity. By promoting satiety and reducing food intake, it can help patients achieve and maintain weight loss, which is critical for managing obesity and its associated complications.

Like other GLP-1R agonists, Orforglipron may have cardiovascular benefits, such as lowering blood pressure and improving lipid profiles. This makes it an attractive option for diabetic patients who are at higher risk for cardiovascular disease.

Emerging research suggests that GLP-1R agonists may have neuroprotective effects and may be beneficial in neurodegenerative diseases such as Alzheimer's disease. While this application is still under investigation, Orforglipron may be a candidate for such a therapeutic strategy.

Unlike peptide-based GLP-1 agonists, Orforglipron can be taken orally, significantly improving patient compliance and convenience. Its effects on insulin secretion are glucose-dependent, reducing the risk of hypoglycemia, a common problem with many diabetes medications. Its ability to promote weight loss offers a dual benefit for patients managing both diabetes and obesity.

Clinical trials will be critical to determining the safety and efficacy of Orforglipron. Preliminary studies have shown that it is well tolerated and has a safety profile similar to other GLP-1R agonists. Common side effects include gastrointestinal discomfort such as nausea and diarrhea, which are usually mild and transient.

References

2020. 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, 117(46).
DOI: 10.1073/pnas.2014879117

2023. Approved Anti-Obesity Medications in 2022 KSSO Guidelines and the Promise of Phase 3 Clinical Trials: Anti-Obesity Drugs in the Sky and on the Horizon. Journal of Obesity & Metabolic Syndrome, 32(2).
DOI: 10.7570/jomes23032

2024. Effects of once-daily oral orforglipron on weight and metabolic markers: a systematic review and meta-analysis of randomized controlled trials. Archives of Endocrinology and Metabolism, 68.
DOI: 10.20945/2359-4292-2023-0469