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| Targets |
(R)-Fasiglifam itself is the inactive isomer and therefore has no significant biological activity at the GPR40 receptor. The active S-enantiomer, Fasiglifam (TAK-875), targets the Free Fatty Acid Receptor 1 (FFAR1, also known as GPR40), which is a G protein-coupled receptor predominantly expressed in pancreatic beta cells. Activation of GPR40 by the active enantiomer potentiates glucose-stimulated insulin secretion (GSIS). (R)-Fasiglifam is used as an inactive control.
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| ln Vitro |
In vitro, (R)-Fasiglifam is the inactive isomer of the GPR40 agonist Fasiglifam (TAK-875). While Fasiglifam (active S-enantiomer) potently activates GPR40 with an EC50 of 72 nM, (R)-Fasiglifam has minimal or no activity at the receptor. It serves as an essential negative control in cellular assays to confirm that the observed effects (e.g., calcium flux, insulin secretion) are specifically mediated by GPR40 activation and not due to off-target effects or vehicle components.
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| ln Vivo |
As the inactive isomer, (R)-Fasiglifam has no relevant in vivo activity in standard pharmacological models. The active enantiomer, Fasiglifam (TAK-875), has been studied in animal models of type 2 diabetes (e.g., Zucker diabetic fatty (ZDF) rats). In these models, Fasiglifam (3-30 mg/kg, p.o.) lowers plasma glucose levels and increases plasma insulin in a glucose-dependent manner. (R)-Fasiglifam is used as an inactive control in such studies to confirm that the glucose-lowering effects are due to GPR40 activation.
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| Enzyme Assay |
A standard non-cellular binding assay for GPR40 agonists is a radioligand binding assay using 3H-labeled fasiglifam (or an equivalent) and membranes prepared from CHO-K1 cells overexpressing human GPR40. The membranes are incubated with 0.5-2 nM of the radioligand and varying concentrations of the test compound (Fasiglifam or (R)-Fasiglifam). Bound radioligand is separated by filtration, and radioactivity is counted. The half-maximal inhibitory concentration (IC50) is calculated. (R)-Fasiglifam is expected to have no significant inhibition.
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| Cell Assay |
A functional cellular assay for GPR40 agonism is a calcium mobilization assay. CHO-K1 cells stably expressing human GPR40 are loaded with a fluorescent calcium indicator dye (e.g., Fluo-4 or Fura-2). The cells are treated with varying concentrations of the test compound (Fasiglifam or (R)-Fasiglifam). The change in fluorescence is measured by a fluorometric imaging plate reader (FLIPR). The half-maximal effective concentration (EC50) is calculated. (R)-Fasiglifam typically shows no significant calcium flux, while the active S-enantiomer has an EC50 of ~72 nM.
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| Animal Protocol |
In an in vivo study of type 2 diabetes, Zucker diabetic fatty (ZDF) rats are divided into groups and treated with vehicle control, (R)-Fasiglifam (inactive control), and active Fasiglifam (TAK-875). Both test compounds are administered orally at doses of 3-30 mg/kg. Blood glucose and plasma insulin levels are measured at various time points (e.g., 0, 15, 30, 60, 120 minutes) after administration. The active compound is expected to reduce blood glucose and increase insulin secretion, while (R)-Fasiglifam should have no effect, serving as a negative control to confirm that the observed effects are due to the specific stereoselective activation of GPR40 by the S-enantiomer.
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| ADME/Pharmacokinetics |
(R)-Fasiglifam has a molecular weight of 524.63 and a molecular formula of C29H32O7S. As a small molecule, it is expected to have good solubility in DMSO and is typically formulated for in vivo administration using vehicles such as 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline. The pharmacokinetic properties of the active S-enantiomer, Fasiglifam (TAK-875), include good oral bioavailability (approximately 70% in animals) and a half-life of 2-5 hours in rats. The (R)-isomer is expected to have similar PK properties but with no efficacy.
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| Toxicity/Toxicokinetics |
As the inactive isomer of Fasiglifam, (R)-Fasiglifam is expected to have a lower toxicity profile than the active GPR40 agonist. The active S-enantiomer, Fasiglifam (TAK-875), was discontinued in clinical development due to liver safety concerns (elevated liver enzymes) in some patients. Therefore, (R)-Fasiglifam, while inactive, may still carry a similar risk for off-target effects. It should be handled with standard laboratory safety precautions, including wearing gloves and avoiding inhalation. It is not intended for human consumption.
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| References |
[1]. Nagatake T, et al. 17,18-EpETE-GPR40 axis ameliorates contact hypersensitivity by inhibiting neutrophil mobility in mice and cynomolgus macaques. J Allergy Clin Immunol. 2017 Dec 26. pii: S0091-6749(17)32949-4.
[2]. Yoshiyuki Tsujihata, et al. TAK-875, an Orally Available GPR40/FFA1 Agonist Enhances Glucose-Dependent Insulin Secretion and Improves Both Postprandial and Fasting Hyperglycemia in Type 2 Diabetic Rats. JPET July 13, 2011 [3]. Tsujihata Y,et al. TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.J Pharmacol Exp [4]. Urano Y, et al. Comparative hepatic transcriptome analyses revealed possible pathogenic mechanisms of fasiglifam (TAK-875)-induced acute liver injury in mice. Chem Biol Interact. 2018 Sep 20;296:185-197. |
| Additional Infomation |
(R)-Fasiglifam ((R)-TAK-875; CAS 1234474-57-7) is the inactive R-enantiomer of the active GPR40 agonist Fasiglifam (TAK-875). Fasiglifam was a potential first-in-class oral antidiabetic agent that acts by potentiating glucose-stimulated insulin secretion in pancreatic beta cells via activation of GPR40. It advanced into Phase 3 clinical trials for type 2 diabetes but was discontinued in 2014 due to hepatotoxicity concerns in a subset of patients. (R)-Fasiglifam is used as an analytical reference and experimental control to validate the specific mechanism of action of Fasiglifam. It is strictly a research chemical and is not approved for any clinical indication.
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| Molecular Formula |
C29H32O7S
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| Molecular Weight |
524.63
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| Exact Mass |
524.186
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| CAS # |
1234474-57-7
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| Related CAS # |
Fasiglifam;1000413-72-8; 1234474-57-7; 1374598-80-7
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| PubChem CID |
71457285
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| Appearance |
White to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
739.1±60.0 °C at 760 mmHg
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| Flash Point |
400.8±32.9 °C
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| Vapour Pressure |
0.0±2.6 mmHg at 25°C
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| Index of Refraction |
1.587
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| LogP |
4.36
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
37
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| Complexity |
828
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S(C)(CCCOC1C=C(C)C(=C(C)C=1)C1C=CC=C(C=1)COC1C=CC2=C(C=1)OC[C@@H]2CC(=O)O)(=O)=O
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| InChi Key |
BZCALJIHZVNMGJ-QHCPKHFHSA-N
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| InChi Code |
InChI=1S/C29H32O7S/c1-19-12-25(34-10-5-11-37(3,32)33)13-20(2)29(19)22-7-4-6-21(14-22)17-35-24-8-9-26-23(15-28(30)31)18-36-27(26)16-24/h4,6-9,12-14,16,23H,5,10-11,15,17-18H2,1-3H3,(H,30,31)/t23-/m0/s1
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| Chemical Name |
2-[(3R)-6-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid
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| Synonyms |
1234474-57-7; 3-Benzofuranacetic acid, 6-[[2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy][1,1'-biphenyl]-3-yl]methoxy]-2,3-dihydro-, (3R)-; (R)-Fasiglifam; (R)-(-)-TAK-875; (R)-2-(6-((2',6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)-[1,1'-biphenyl]-3-yl)methoxy)-2,3-dihydrobenzofuran-3-yl)acetic 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: 100 mg/mL (190.61 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 | 1.9061 mL | 9.5305 mL | 19.0611 mL | |
| 5 mM | 0.3812 mL | 1.9061 mL | 3.8122 mL | |
| 10 mM | 0.1906 mL | 0.9531 mL | 1.9061 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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