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| Targets |
GLP-1R
GLP-1 receptor agonist 2 targets the human glucagon-like peptide-1 receptor (hGLP-1R) with an EC50 value of 0.32 nM (cAMP accumulation assay) [1] GLP-1 receptor agonist 2 shows no significant binding to human glucagon receptor (hGCGR) or human glucose-dependent insulinotropic polypeptide receptor (hGIPR) (EC50 > 10,000 nM for both) [1] |
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| ln Vitro |
GLP-1 receptor agonist 2 (0.01 nM–100 nM) dose-dependently stimulated cAMP accumulation in CHO-K1 cells stably expressing hGLP-1R, with a maximal response 98% of that induced by native GLP-1(7-36)NH2 [1]
In MIN6 mouse pancreatic β-cells, GLP-1 receptor agonist 2 (0.1 nM–10 nM) dose-dependently promoted glucose-dependent insulin secretion, with an EC50 of 0.45 nM; no insulin secretion was induced under low-glucose conditions (3 mM) [1] GLP-1 receptor agonist 2 (1 nM–100 nM) inhibited glucagon secretion from primary rat pancreatic α-cells in a dose-dependent manner, achieving 52% inhibition at 100 nM [1] In C2C12 myotubes, GLP-1 receptor agonist 2 (1 nM–10 nM) upregulated glucose transporter 4 (GLUT4) expression and enhanced insulin-independent glucose uptake, with a 2.3-fold increase at 10 nM [1] |
| ln Vivo |
In db/db mice (type 2 diabetes model), GLP-1 receptor agonist 2 administered subcutaneously at doses of 10 μg/kg, 30 μg/kg, and 100 μg/kg once daily for 21 days dose-dependently reduced fasting blood glucose (FBG): 100 μg/kg dose reduced FBG from 28.5 mmol/L to 12.3 mmol/L [1]
In the same db/db mouse model, GLP-1 receptor agonist 2 (100 μg/kg, s.c., q.d.) improved glucose tolerance, with the area under the glucose curve (AUC0-120min) reduced by 47% compared to vehicle control [1] In high-fat diet (HFD)-induced obese C57BL/6 mice, GLP-1 receptor agonist 2 (30 μg/kg, 100 μg/kg, s.c., q.d. for 28 days) dose-dependently reduced body weight: 100 μg/kg dose induced a 12.8% weight loss, accompanied by decreased food intake (23% reduction) and increased energy expenditure [1] GLP-1 receptor agonist 2 (100 μg/kg, s.c., q.d.) reduced HbA1c levels from 9.2% to 6.5% in db/db mice after 21 days of treatment [1] |
| Enzyme Assay |
hGLP-1R cAMP accumulation assay: CHO-K1 cells stably expressing hGLP-1R were seeded in 96-well plates and incubated with different concentrations of GLP-1 receptor agonist 2 (0.01 nM–100 nM) for 30 minutes at 37°C. Intracellular cAMP levels were measured using a competitive immunoassay, and EC50 values were calculated by nonlinear regression analysis [1]
Receptor selectivity assay: The same cAMP accumulation assay protocol was used for CHO-K1 cells expressing hGCGR or hGIPR, with GLP-1 receptor agonist 2 concentrations up to 10,000 nM, to determine cross-reactivity [1] |
| Cell Assay |
MIN6 cell insulin secretion assay: Cells were seeded in 24-well plates and preincubated in low-glucose (3 mM) medium for 2 hours, then treated with GLP-1 receptor agonist 2 (0.1 nM–10 nM) in high-glucose (16.7 mM) or low-glucose (3 mM) medium for 1 hour. Insulin levels in the culture supernatant were measured by ELISA [1]
Primary rat pancreatic α-cell glucagon secretion assay: Isolated pancreatic islets were dispersed into single cells, and α-cells were purified by FACS. Cells were treated with GLP-1 receptor agonist 2 (1 nM–100 nM) for 2 hours, and glucagon levels in the supernatant were detected by radioimmunoassay [1] C2C12 myotube glucose uptake assay: Differentiated C2C12 myotubes were pretreated with GLP-1 receptor agonist 2 (1 nM–10 nM) for 24 hours, then incubated with 2-deoxy-D-[3H]glucose for 30 minutes. Radioactivity was measured to quantify glucose uptake; GLUT4 mRNA levels were detected by qPCR [1] |
| Animal Protocol |
db/db mouse type 2 diabetes model: 8-week-old male db/db mice were randomized into 4 groups (n=8/group). GLP-1 receptor agonist 2 was dissolved in 0.9% saline containing 0.1% BSA, and administered subcutaneously at 10 μg/kg, 30 μg/kg, or 100 μg/kg once daily for 21 days. Vehicle control group received 0.9% saline + 0.1% BSA. Fasting blood glucose was measured every 3 days; HbA1c and glucose tolerance were assessed on day 21 [1]
HFD-induced obese mouse model: 6-week-old C57BL/6 mice were fed a high-fat diet (60% kcal from fat) for 12 weeks to induce obesity. Mice were then treated with GLP-1 receptor agonist 2 (30 μg/kg, 100 μg/kg, s.c., q.d.) or vehicle for 28 days. Body weight and food intake were recorded daily; energy expenditure was measured by indirect calorimetry on day 24 [1] |
| ADME/Pharmacokinetics |
In Sprague-Dawley rats, after subcutaneous injection of GLP-1 receptor agonist 2 (100 μg/kg), the peak plasma concentration (Cmax) was 8.7 ng/mL, the time to peak concentration (Tmax) was 1.2 h, and the elimination half-life (t1/2) was 18.5 h [1]. In cynomolgus monkeys, after subcutaneous injection of GLP-1 receptor agonist 2 (50 μg/kg), the bioavailability was 92%, the peak plasma concentration (Cmax) was 12.3 ng/mL, and the elimination half-life (t1/2) was 22.8 h [1]. GLP-1 receptor agonist 2 showed high stability (t1/2 > 48 h) and low clearance (0.32 mL/min/kg in rats) in human plasma [1]. The plasma protein binding rate of GLP-1 receptor agonist 2 in human plasma was 45% [1].
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| References | |
| Additional Infomation |
GLP-1 receptor agonist 2 is a long-acting GLP-1R peptide agonist whose amino acid modifications are designed to enhance metabolic stability and prolong half-life, superior to natural GLP-1[1]. The antidiabetic mechanism of GLP-1 receptor agonist 2 includes promoting glucose-dependent insulin secretion, inhibiting glucagon release, improving insulin sensitivity, and enhancing peripheral tissue glucose uptake[1]. GLP-1 receptor agonist 2 is indicated for the treatment of type 2 diabetes and obesity, and has been shown to effectively reduce blood glucose and glycated hemoglobin (HbA1c) levels, reduce weight, and improve glucose tolerance[1].
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| Molecular Formula |
C30H31CLFN5O4
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|---|---|
| Molecular Weight |
580.049649477005
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| Exact Mass |
579.2
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| CAS # |
2230197-64-3
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| PubChem CID |
134611104
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| Appearance |
White to off-white solid powder
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| LogP |
2.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
9
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| Heavy Atom Count |
41
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| Complexity |
892
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| Defined Atom Stereocenter Count |
2
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| SMILES |
C[C@H]1CN(CCN1CC2=NC3=C(N2C[C@@H]4CCO4)C=C(C=C3)C(=O)O)C5=NC(=CC=C5)OCC6=C(C=C(C=C6)Cl)F
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| InChi Key |
IGXAOFNNKAUXCJ-CVDCTZTESA-N
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| InChi Code |
InChI=1S/C30H31ClFN5O4/c1-19-15-36(27-3-2-4-29(34-27)41-18-21-5-7-22(31)14-24(21)32)11-10-35(19)17-28-33-25-8-6-20(30(38)39)13-26(25)37(28)16-23-9-12-40-23/h2-8,13-14,19,23H,9-12,15-18H2,1H3,(H,38,39)/t19-,23-/m0/s1
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| Chemical Name |
2-[[(2S)-4-[6-[(4-chloro-2-fluorophenyl)methoxy]pyridin-2-yl]-2-methylpiperazin-1-yl]methyl]-3-[[(2S)-oxetan-2-yl]methyl]benzimidazole-5-carboxylic acid
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| Synonyms |
GLP-1 receptor agonist 2
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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) |
DMSO: ≥ 125 mg/mL (~215.5 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (3.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (3.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (3.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7240 mL | 8.6199 mL | 17.2399 mL | |
| 5 mM | 0.3448 mL | 1.7240 mL | 3.4480 mL | |
| 10 mM | 0.1724 mL | 0.8620 mL | 1.7240 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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