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| Targets |
(1R)-GLP-1 receptor agonist 12 targets the glucagon-like peptide-1 receptor (GLP-1R), a G protein-coupled receptor (GPCR) expressed on pancreatic beta-cells, as well as in the brain, gut, and other tissues. Activation of GLP-1R by the agonist stimulates glucose-dependent insulin secretion from pancreatic beta-cells, suppresses glucagon release from pancreatic alpha-cells, slows gastric emptying, and reduces appetite. In preclinical studies, GLP-1R agonist 12 (the racemate or the isomer mixture) has demonstrated potent agonistic activity and the ability to stimulate insulin secretion and enhance beta-cell function. The compound exhibits significant agonistic activity, which can stimulate insulin secretion and enhance beta-cell function. As a small molecule GLP-1R agonist, it binds to the orthosteric binding site of the receptor or an allosteric site, leading to receptor activation and downstream signaling through the cAMP/PKA pathway. Unlike the (1S) isomer, the (1R) isomer is designed to have improved pharmacological properties.
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| ln Vitro |
In vitro activity of (1R)-GLP-1 receptor agonist 12 has been characterized in cell-based functional assays. The compound is an isomer of GLP-1 receptor agonist 12, which exhibits potent agonistic activity at the GLP-1 receptor. In standard assays using GLP-1R-expressing cell lines (e.g., HEK-293 cells stably transfected with human GLP-1R), the compound stimulates intracellular cAMP accumulation, a key second messenger downstream of GLP-1R activation. The EC₅0 for the racemic mixture or the specific isomer is likely in the low nanomolar to sub-nanomolar range, based on the reported potency of related GLP-1R agonists. Additionally, the compound is expected to promote glucose-dependent insulin secretion in pancreatic beta-cell lines (e.g., INS-1 or MIN6 cells) and enhance beta-cell proliferation and survival. The compound also improves glucose-stimulated insulin secretion. Compared to the selective GLP-1R agonist liraglutide, the dual GLP-1R/glucagon receptor agonist (a related compound, peptide 12) showed superior weight loss effects in non-human primates. The (1R) isomer specifically is the active isomer of GLP-1 receptor agonist 12, designed to have improved efficacy and safety.
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| ln Vivo |
In vivo studies have demonstrated the efficacy of GLP-1R agonist 12 in animal models of type 2 diabetes and obesity. In diet-induced obese (DIO) mice and in non-human primates (NHPs), the dual GLP-1R/glucagon receptor agonist peptide 12 (which may be related to or the same as agonist 12) has demonstrated superior weight loss effects compared to the selective GLP-1R agonist liraglutide, even when administered at a 5-fold lower dose. In type 2 diabetic animals, the compound reduces blood glucose levels, improves HbA1c, and enhances beta-cell function. Toxicology studies in rats and monkeys have shown an overall reasonable clean profile with no significant effects on hERG current, suggesting low cardiovascular risk. Efficacy studies in healthy and diseased NHPs have indicated that the compound has the potential to provide significant improvement over GLP-1R-selective agonists in several markers associated with metabolic syndrome. While specific data for the (1R) isomer are not disclosed, the racemic compound or the isomer mixture has been evaluated in dose-limiting toxicology studies.
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| Enzyme Assay |
The GLP-1 receptor binding and functional activity of (1R)-GLP-1 receptor agonist 12 can be assessed using standard cell-free or cell-based receptor binding assays. A standard protocol for radioligand binding assay: (1) Prepare membranes from HEK-293 cells stably expressing the human GLP-1 receptor. (2) Incubate membranes (10-50 ug protein/well) with a fixed concentration of a radiolabeled high-affinity GLP-1R ligand, such as [¹2⁵I]GLP-1 (7-36) amide (20-50 pM) or [3H]compound, in assay buffer (50 mM HEPES, pH 7.4, 5 mM MgCl2, 1 mM CaCl2, 0.2% BSA, and 0.1 mM PMSF) at 25degC for 60-90 minutes. (3) Add varying concentrations of test compound (0.01 nM to 10 uM) to compete for receptor binding. (4) Incubate, then harvest by rapid vacuum filtration through GF/B glass fiber filters presoaked in 0.3% polyethylenimine (PEI). (5) Wash filters with ice-cold buffer and measure retained radioactivity by liquid scintillation or gamma counting. (6) Calculate specific binding (total minus non-specific binding, determined in the presence of 1 uM unlabeled GLP-1) and plot competition curves. (7) Calculate IC₅0 and Kᵢ values using nonlinear regression (Cheng-Prusoff equation). (8) For functional activity (agonist potency), use a cAMP accumulation assay (see cell-based protocol below).
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| Cell Assay |
For the (1R)-GLP-1 receptor agonist 12, the standard cellular assay for measuring functional activity is the cAMP accumulation assay in GLP-1R-expressing cells. (1) Culture HEK-293 cells stably transfected with the human GLP-1 receptor (GLP-1R-HEK293 cells) in DMEM with 10% FBS, 1% penicillin/streptomycin, and appropriate selection antibiotics (e.g., G418, 400 ug/mL) at 37degC in 5% CO2. (2) When cells reach 70-80% confluence, detach cells with trypsin-EDTA and seed into white 96-well assay plates (20,000-40,000 cells/well) in serum-free medium. (3) Incubate for 4-24 hours to allow receptor expression. (4) Prepare (1R)-GLP-1 receptor agonist 12 as a 10 mM stock in DMSO, then serially dilute in assay buffer (e.g., PBS with 0.5 mM IBMX, a phosphodiesterase inhibitor). Final concentration range: 0.01 nM to 10 uM (ten 3- or 10-fold dilutions). (5) Aspirate medium from wells, add 25-50 uL of compound dilutions to each well (in triplicate). Include positive control wells (GLP-1(7-36) amide, 0.1-100 nM) and negative control wells (vehicle only, 0.1% DMSO). (6) Incubate at 37degC for 30-45 minutes. (7) Lyse cells and detect intracellular cAMP using a homogeneous time-resolved fluorescence (HTRF) cAMP kit (Cisbio) or a chemiluminescent cAMP-Glo™ assay (Promega) following the manufacturer's instructions. (8) Read the signal using a microplate reader. (9) Calculate the EC₅0 (the concentration required to achieve 50% of the maximal response) by plotting the normalized cAMP response versus log concentration of the compound using four-parameter logistic regression. (10) The compound is expected to have an EC₅0 in the low nanomolar range.
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| Animal Protocol |
The in vivo efficacy of GLP-1 receptor agonists, including the related dual GLP-1R/glucagon receptor agonist peptide 12, has been evaluated in non-human primates (NHPs). A standard protocol: (1) Use healthy adult cynomolgus macaques (Macaca fascicularis) or rhesus macaques, or diet-induced obese (DIO) NHPs. (2) Acclimate animals for 2-4 weeks. (3) Administer the test compound by subcutaneous (SC) injection once daily (QD) or twice daily (BID) at doses ranging from 0.1 to 10 mg/kg. (4) For control groups, administer vehicle (e.g., 10% DMSO, 40% PEG300, 5% Tween 80, 45% saline for small molecules, or saline for peptides) or a positive control (liraglutide at 0.5 mg/kg, QD). (5) For pharmacodynamic assessments: (a) Monitor body weight twice weekly; (b) For oral glucose tolerance test (OGTT): fast animals overnight (14-16 hours), administer glucose (1-2 g/kg) by oral gavage, and collect blood samples at -30, 0, 15, 30, 60, 90, 120 minutes post-glucose for measurement of blood glucose, insulin, and C-peptide; (c) Collect blood at trough (pre-dose) and at various time points post-dose for measurement of HbA1c, fructosamine, and lipid profile (triglycerides, cholesterol); (d) For food intake measurement, animals are single-housed and food consumption (g/day) is measured daily. (6) For pharmacokinetic assessment, collect blood samples at multiple time points (pre-dose, 0.25, 0.5, 1, 2, 4, 6, 8, 12, 24 hours) for determination of plasma compound concentration by LC-MS/MS. (7) Continue the study for 2-12 weeks. (8) At study termination, euthanize animals and collect pancreas, liver, and other tissues for histopathology and immunohistochemistry (e.g., beta-cell mass, proliferation markers). (9) Efficacy: The dual GLP-1R/glucagon receptor agonist (peptide 12) demonstrated superior weight loss and HbA1c improvement compared to liraglutide despite being administered at a 5-fold lower dose.
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| ADME/Pharmacokinetics |
Specific pharmacokinetic data for (1R)-GLP-1 receptor agonist 12 are not disclosed in the public domain. However, as a small molecule (MW 570.61), it is expected to have improved oral bioavailability compared to peptide-based GLP-1 receptor agonists. The compound contains a fluorine atom (C31H31FN₆O4), which may contribute to metabolic stability. In preclinical studies with related compounds, no significant effects on hERG current have been observed, suggesting low risk of cardiac QT prolongation. The racemic compound or the isomer mixture has been evaluated in dose-limiting toxicology studies in rat and monkey, with an overall reasonable clean profile. The compound is formulated as a powder for storage at -20degC (stable for up to 3 years) or at 4degC (stable for up to 2 years). For experimental use, it is soluble in DMSO (≥25 mg/mL) to prepare stock solutions. In-solvent stability: 6 months at -80degC, 1 month at -20degC. For in vivo dosing, formulations may include 10% DMSO, 40% PEG300, 5% Tween 80, and 45% saline to achieve a clear solution. No data are available on the absorption, distribution, metabolism, excretion, or half-life of the (1R) isomer specifically.
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| Toxicity/Toxicokinetics |
Published toxicological data for (1R)-GLP-1 receptor agonist 12 indicate an overall reasonable clean profile in dose-limiting toxicology studies in rats and monkeys. No significant effects on hERG current were observed, suggesting low risk of cardiac arrhythmias. However, specific adverse effect data, including LD₅0 values, target organ toxicity, and carcinogenicity, have not been disclosed. As with other GLP-1 receptor agonists, potential risks may include gastrointestinal side effects (nausea, vomiting, diarrhea) due to the pharmacological effect of slowing gastric emptying. Pancreatitis and medullary thyroid carcinoma (MTC) have been reported for some GLP-1 receptor agonists in clinical use, but long-term safety data for this specific small molecule are not available. The compound is intended for research use only and is not approved for human therapeutic use. Standard safety precautions for handling small molecule kinase inhibitors/GPCR modulators should be followed: use of personal protective equipment (gloves, lab coat, safety goggles), working in a well-ventilated area (fume hood), and avoiding skin contact, ingestion, and inhalation. The compound is not a drug and is not intended for human consumption.
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| References | |
| Additional Infomation |
(1R)-GLP-1 receptor agonist 12 (CAS 2775376-51-5) is a small molecule GLP-1 receptor agonist currently in preclinical research. It is the (1R) isomer of GLP-1 receptor agonist 12 , and the compound is likely a non-peptide agonist designed to overcome the limitations of peptide-based GLP-1 analogues, which require parenteral administration. The compound may have dual GLP-1R/glucagon receptor agonist activity, as related compound “peptide 12” has been described as a dual agonist. The development of small molecule GLP-1R agonists is a major focus of the pharmaceutical industry for the treatment of type 2 diabetes and obesity. The compound's significant agonistic activity stimulates insulin secretion and enhances beta-cell function. Efficacy studies in healthy and diseased non-human primates (NHPs) have indicated that the compound (or the related dual agonist) has the potential to provide significant improvement over GLP-1R-selective agonists in several markers associated with metabolic syndrome, with no significant effect on hERG current and an overall reasonable clean profile in dose-limiting toxicology studies in rat and monkey. The (1R)-GLP-1 receptor agonist 12 is not an FDA-approved drug, has not entered clinical trials, and is strictly for research use only.
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| Molecular Formula |
C31H31FN6O4
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| Molecular Weight |
570.61
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| CAS # |
2775376-51-5
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| Appearance |
Solid powder
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7525 mL | 8.7626 mL | 17.5251 mL | |
| 5 mM | 0.3505 mL | 1.7525 mL | 3.5050 mL | |
| 10 mM | 0.1753 mL | 0.8763 mL | 1.7525 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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