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| Targets |
GPR40 agonist 6 specifically targets the free fatty acid receptor 1 (FFAR1, also known as GPR40), a G protein-coupled receptor primarily expressed in pancreatic beta cells, as well as in enteroendocrine cells and certain brain regions. GPR40 is activated by medium- and long-chain free fatty acids and plays a key role in amplifying glucose-stimulated insulin secretion (GSIS). GPR40 agonist 6 binds to GPR40 with high affinity and selectivity, activating the Gq signaling pathway, leading to increased intracellular calcium and enhanced insulin secretion.
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| ln Vitro |
At 5 µM, compound 7a, or GPR40 agonist 6, exhibits a highly favorable ADME profile with no discernible inhibitory effect on the major cytochrome P450 isoforms (1A2, 2C9, 2C19, 2D6, and 3A4) [1]. The following is the ADME curve of GPR40 Agonist 6 (Compound 7a): a. Human plasma protein binding (98.6%); b. Water solubility (PBS, pH 7.4); c. Microsomal stability (mouse, t1/2); d. AB permeability (Caco-2, cm·s-1); d. 15.2 • 10-6; a. Each value is the mean of n = 4, measured at c = 1 µM. b Each value represents the n = 2 mean. c Every value is the n = 5 mean, calculated at c = 2 µM. The average of n = 2 measured at c = 10 µM is represented by each value.
In vitro, GPR40 agonist 6 is a potent and selective agonist of GPR40, with an EC50 of 0.058 microM (58 nM). In cell-based assays using GPR40-expressing cells, the compound stimulates calcium mobilization and increases insulin secretion in a glucose-dependent manner. It exhibits a favorable ADME (absorption, distribution, metabolism, excretion) profile and shows no significant inhibition of major cytochrome P450 (CYP) isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at 5 microM, indicating a low potential for drug-drug interactions. |
| ln Vivo |
In vivo, GPR40 agonist 6 has demonstrated the ability to enhance glucose-stimulated insulin secretion and improve glucose tolerance in animal models of type 2 diabetes. By activating GPR40, the compound amplifies insulin release only when blood glucose levels are elevated, reducing the risk of hypoglycemia compared to sulfonylureas. It is a valuable research tool for studying the therapeutic potential of GPR40 agonists for the treatment of type 2 diabetes. The compound is in the preclinical stage of development.
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| Enzyme Assay |
For in vitro receptor binding and activation assays, a standard protocol uses a calcium mobilization assay. CHO-K1 cells stably expressing human GPR40 are seeded in 96-well black-walled clear-bottom plates. Cells are loaded with a calcium-sensitive fluorescent dye (e.g., Fluo-4 AM or Calcium 4 dye) in assay buffer (Hanks' Balanced Salt Solution with 20 mM HEPES, 0.1% BSA, and 2.5 mM probenecid) for 60 minutes at 37degC. Varying concentrations of GPR40 agonist 6 (0.01 nM - 10 microM) are added, and the fluorescence signal is measured using a fluorescence plate reader. The EC50 is calculated from the dose-response curve. For selectivity, the compound is tested against other fatty acid receptors (GPR41, GPR43, GPR119).
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| Cell Assay |
For in vitro cell-based assays, INS-1E rat insulinoma cells or isolated mouse pancreatic islets are used. Cells or islets are pre-incubated in Krebs-Ringer bicarbonate buffer (KRB) with 2.8 mM glucose for 1 hour. They are then treated with varying concentrations of GPR40 agonist 6 (0.001-10 microM) in the presence of 5-20 mM glucose for 30-60 minutes. Supernatants are collected, and insulin concentration is measured by ELISA or RIA. To confirm GPR40 dependence, the assay can be performed in the presence of a GPR40 antagonist (e.g., DC260126). The EC50 for insulin secretion is calculated. For ADME studies, the compound is incubated with human liver microsomes to assess metabolic stability.
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| Animal Protocol |
For in vivo animal studies, a mouse or rat model of type 2 diabetes (e.g., db/db mice, high-fat diet-fed mice, or streptozotocin-treated rats) is used. GPR40 agonist 6 is administered orally by gavage at doses of 1-30 mg/kg. An oral glucose tolerance test (OGTT) is performed 30-60 minutes after compound administration. Blood glucose is measured at 0, 15, 30, 60, 90, and 120 minutes after glucose challenge. Plasma insulin levels are measured at selected time points by ELISA. The compound's effect on glucose tolerance (AUC reduction) and insulin secretion (increase) is calculated. Body weight and food intake are also monitored for longer-term studies (e.g., 4 weeks).
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| ADME/Pharmacokinetics |
GPR40 agonist 6 has a molecular weight of 337.37 g/mol and a molecular formula of C20H19NO4, with a favorable ADME profile. The compound shows good oral bioavailability and metabolic stability. It exhibits no significant inhibition of major CYP450 isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at 5 microM, suggesting a low potential for drug-drug interactions. The elimination half-life in preclinical species is likely 2-6 hours, supporting once- or twice-daily dosing. Detailed PK parameters (Cmax, T1/2, AUC, clearance) are available in the primary literature for Compound 7a.
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| Toxicity/Toxicokinetics |
Specific toxicology data for GPR40 agonist 6 is not publicly available, as it is a preclinical research compound. As a GPR40 agonist, potential mechanism-based adverse effects include gastrointestinal side effects (nausea, diarrhea) similar to other GPR40 agonists. Because GPR40 activation amplifies glucose-stimulated insulin secretion, the risk of hypoglycemia is low but still a consideration. Standard safety pharmacology studies would include a hERG assay to rule out QT prolongation, and a 14-28 day repeat-dose toxicity study in rats and dogs to determine the no-observed-adverse-effect level (NOAEL). The compound is for research use only and is not approved for human use.
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| References | |
| Additional Infomation |
GPR40 agonist 6 is a research compound and is not approved for clinical use. It is also known as Compound 7a. GPR40 is an attractive target for the treatment of type 2 diabetes because its activation promotes glucose-stimulated insulin secretion without causing hypoglycemia, a common side effect of sulfonylureas. Unlike GLP-1 receptor agonists, GPR40 agonists are small molecules that can be taken orally, offering a potential advantage in patient convenience and cost. GPR40 agonist 6 is a valuable tool for studying the structure-activity relationships of GPR40 agonists and for understanding the role of GPR40 in glucose homeostasis. It is for research use only.
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| Molecular Formula |
C20H19NO4
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| Molecular Weight |
337.369165658951
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| Exact Mass |
337.131
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| CAS # |
1798751-25-3
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| PubChem CID |
86803224
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| Appearance |
White to off-white solid powder
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| LogP |
3.7
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
25
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| Complexity |
416
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(CCC(O)=O)=CC=C(OCC2=C(C)OC(C3=CC=CC=C3)=N2)C=C1
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| InChi Key |
BVILYIQBHXIHEN-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H19NO4/c1-14-18(21-20(25-14)16-5-3-2-4-6-16)13-24-17-10-7-15(8-11-17)9-12-19(22)23/h2-8,10-11H,9,12-13H2,1H3,(H,22,23)
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| Chemical Name |
3-[4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenyl]propanoic acid
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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 (~370.51 mM)
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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 | 2.9641 mL | 14.8205 mL | 29.6410 mL | |
| 5 mM | 0.5928 mL | 2.9641 mL | 5.9282 mL | |
| 10 mM | 0.2964 mL | 1.4821 mL | 2.9641 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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