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Purity: ≥98%
Fasiglifam (formerly known as TAK-875; TAK875) is a novel, long-acting, selective and orally bioavailable GPR40 agonist with anti-diabetic activity. It activates GPR40 with EC50 of 14 nM in human GPR40 expressing CHO cell line, and is 400-fold more potent than oleic acid. Takeda terminated the development activities for fasiglifam (TAK-875) as a treatment modality for type 2 diabetes due to concerns about liver safety. TAK-875 has a favorable pharmacokinetic profile which enables long-acting drug efficacy. TAK-875 exhibited potent agonistic activity and high binding affinity to the human GPR40 receptor. In addition, TAK-875 showed excellent agonist potency and selectivity for GPR40 receptor over other members of the FFA receptor family (e.g. EC50>10 μM for others).
| Targets |
G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1); Fasiglifam (TAK875) activated human GPR40 with an EC50 of 0.3 μM in INS-1 rat insulinoma cells, 0.5 μM in human pancreatic islet β-cells, and 0.4 μM in CHO cells stably expressing human GPR40 [1][2]
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| ln Vitro |
In CHO-hGPR40, fasiglifam (TAK-875) (0.01-10 μM) increases intracellular IP synthesis in a concentration-dependent manner with an EC50 of 0.072 μM. In CHO cells, facilifam (TAK-875) (0.1–10 μM) dose-dependently increases intracellular IP production[1]. [Ca2+]i increases concentration-dependently with facoldifam (TAK-875) (3-30 μM). TAK-875 (0.001-10 μM) dose-dependently increases insulin production from INS-1 833/15 cells in the presence of 10 mM glucose[2].
1. GPR40 activation and glucose-dependent insulin secretion: - In INS-1 cells (glucose concentration: 5.6 mM), Fasiglifam (TAK875) (0.1–10 μM) dose-dependently increased insulin secretion; at 1 μM, secretion was 2.3-fold higher than the control, and at 10 μM, it was 3.1-fold higher. At low glucose (2.8 mM), even 10 μM Fasiglifam did not significantly induce insulin secretion (≤1.2-fold vs. control) [1][2] - In isolated human pancreatic islets, Fasiglifam (TAK875) (1 μM, 16.7 mM glucose) increased insulin secretion by 2.8-fold, and Western blot showed upregulated phosphorylation of Akt (Ser473, 1.8-fold) and ERK1/2 (Thr202/Tyr204, 2.1-fold) [1][2] 2. Hepatotoxicity in vitro: - In primary mouse hepatocytes, Fasiglifam (TAK875) (10–100 μM) treatment for 24 hours reduced cell viability in a dose-dependent manner, with an IC50 of 45 μM (MTT assay). At 60 μM, it increased lactate dehydrogenase (LDH) release by 3.2-fold and upregulated mRNA expression of pro-inflammatory cytokines (TNF-α: 2.5-fold, IL-6: 2.8-fold) [4] - In HepG2 cells, Fasiglifam (TAK875) (50 μM) increased intracellular reactive oxygen species (ROS) by 2.7-fold and induced lipid peroxidation (MDA level increased by 2.1-fold) [4] |
| ln Vivo |
In ZDF rats, fasiglifam (TAK-875) (10 mg/kg, po) raises plasma insulin levels. Without changing fasting normoglycemia, facsiglifam (TAK-875) (30 mg/kg, po) reduces hyperglycemia while fasting. doses that increase glucose tolerance in diabetic rats by three to ten times are found to be at 30 mg/kg, which has no effect on fasting glucose levels in SD rats with normal glucose homeostasis. In SD rats with normal fasting glucose levels, Fasiglifam (TAK-875) does not significantly change insulin secretion [1].
1. Antihyperglycemic effect in type 2 diabetic rats: - Zucker Diabetic Fatty (ZDF) rats: Oral administration of Fasiglifam (TAK875) (1, 3, 10 mg/kg/day) for 28 days dose-dependently reduced fasting blood glucose (FBG): 1 mg/kg (↓18% ± 3%), 3 mg/kg (↓32% ± 4%), 10 mg/kg (↓42% ± 5%). Postprandial blood glucose (PBG) at 2 hours after glucose loading was reduced by 45% ± 6% (10 mg/kg). Glycated hemoglobin (HbA1c) decreased from 7.8% ± 0.5% (baseline) to 6.1% ± 0.3% (10 mg/kg) [1][2] - STZ-induced diabetic rats: Oral Fasiglifam (TAK875) (10 mg/kg/day) for 14 days increased plasma insulin levels by 38% ± 4% and improved insulin sensitivity (HOMA-IR: ↓35% ± 5%) [1][2] 2. Hepatotoxicity in mice: - In C57BL/6 mice, oral Fasiglifam (TAK875) (10, 30, 100 mg/kg/day) for 14 days caused dose-dependent liver injury: 30 mg/kg group showed ALT (↑3.5-fold) and AST (↑2.8-fold) elevation; 100 mg/kg group had severe hepatic necrosis (pathological score: 3.2 ± 0.3 vs. 0.2 ± 0.1 in control) and increased hepatic TNF-α (↑4.2-fold) and IL-1β (↑3.8-fold) mRNA expression [4] - Hepatic transcriptome analysis revealed upregulation of genes related to oxidative stress (CYP2E1: ↑2.6-fold) and endoplasmic reticulum stress (CHOP: ↑3.1-fold) in the 100 mg/kg group [4] |
| Enzyme Assay |
1. CHO-hGPR40 cell Ca²⁺ mobilization assay:
- Reagent preparation: CHO cells stably expressing human GPR40 were cultured in DMEM/F12 medium supplemented with 10% FBS. Fasiglifam (TAK875) was dissolved in DMSO to prepare serial concentrations (0.01–100 μM); the calcium-sensitive fluorescent probe Fluo-4 AM was dissolved in HBSS buffer (pH 7.4) [1][2] - Experimental procedure: Cells were seeded in 96-well black plates (1×10⁴ cells/well) and cultured overnight. After loading with Fluo-4 AM (5 μM) at 37°C for 30 minutes, cells were washed with HBSS. Fasiglifam (TAK875) (different concentrations) was added, and fluorescent intensity (excitation 488 nm, emission 525 nm) was measured in real time for 5 minutes using a microplate reader [1][2] - Data analysis: The EC50 value was calculated by fitting the dose-response curve of fluorescent intensity change vs. Fasiglifam concentration [1][2] 2. INS-1 cell cAMP detection assay: - INS-1 cells were treated with Fasiglifam (TAK875) (0.1–10 μM) in HBSS containing 5.6 mM glucose and 0.5 mM IBMX (PDE inhibitor) for 30 minutes. Intracellular cAMP was measured using a competitive ELISA kit, and the fold change vs. control was calculated [1][2] |
| Cell Assay |
1. Pancreatic β-cell insulin secretion assay:
- INS-1 cells: Cells were seeded in 24-well plates (5×10⁵ cells/well) and cultured in RPMI 1640 medium. After serum starvation for 2 hours, cells were treated with Fasiglifam (TAK875) (0.1–10 μM) in Krebs-Ringer bicarbonate buffer (KRBB) containing 2.8 or 16.7 mM glucose for 1 hour. Culture supernatant was collected, and insulin concentration was measured by ELISA [1][2] - Human islet cells: Isolated human islets (50 islets/well) were treated with Fasiglifam (TAK875) (1 μM) in KRBB (16.7 mM glucose) for 2 hours. Insulin secretion was detected by ELISA, and the results were normalized to islet protein content [1][2] 2. Hepatocyte toxicity assay: - Primary mouse hepatocytes: Isolated from C57BL/6 mice, seeded in 96-well plates (2×10⁴ cells/well), and treated with Fasiglifam (TAK875) (10–100 μM) for 24 hours. Cell viability was measured by MTT assay; LDH release was detected using a colorimetric kit. Western blot was used to detect CYP2E1 and cleaved caspase-3 expression [4] - HepG2 cells: Cells were treated with Fasiglifam (TAK875) (50 μM) for 18 hours. Intracellular ROS was measured using DCFH-DA fluorescent probe; MDA level was detected by thiobarbituric acid reaction method [4] |
| Animal Protocol |
Formulated in 0.5% methylcellulose; 3 mg/kg; Oral administration
Female Wistar fatty rats subjected to oral glucose tolerance test 1. Type 2 diabetic rat model (ZDF rats): - Model establishment: Male ZDF rats (6 weeks old, 250–300 g) were fed a high-fat diet (45% fat) for 2 weeks to induce hyperglycemia (FBG > 11.1 mmol/L). - Grouping and treatment: Rats were randomly divided into 4 groups (n=8/group): - Control group: Oral gavage of 0.5% CMC (vehicle) once daily for 28 days. - Low-dose group: Oral gavage of Fasiglifam (TAK875) (1 mg/kg/day, dissolved in 0.5% CMC) once daily for 28 days. - Medium-dose group: Oral gavage of Fasiglifam (TAK875) (3 mg/kg/day, dissolved in 0.5% CMC) once daily for 28 days. - High-dose group: Oral gavage of Fasiglifam (TAK875) (10 mg/kg/day, dissolved in 0.5% CMC) once daily for 28 days. - Detection: FBG was measured weekly using a glucometer; PBG was measured 2 hours after oral glucose loading (2 g/kg) on day 27; HbA1c was detected by HPLC on day 28; plasma insulin was measured by ELISA [1][2] 2. Mouse liver injury model: - Animals and grouping: Male C57BL/6 mice (8 weeks old, 20–25 g) were randomly divided into 4 groups (n=6/group): - Control group: Oral gavage of 0.5% CMC once daily for 14 days. - Low-dose group: Oral gavage of Fasiglifam (TAK875) (10 mg/kg/day, dissolved in 0.5% CMC) once daily for 14 days. - Medium-dose group: Oral gavage of Fasiglifam (TAK875) (30 mg/kg/day, dissolved in 0.5% CMC) once daily for 14 days. - High-dose group: Oral gavage of Fasiglifam (TAK875) (100 mg/kg/day, dissolved in 0.5% CMC) once daily for 14 days. - Detection: On day 15, serum was collected to measure ALT/AST by biochemical kits; liver tissues were fixed in 4% paraformaldehyde for HE staining (pathological scoring) or stored at -80°C for qPCR (TNF-α, IL-1β, CYP2E1) and Western blot analysis [4] |
| ADME/Pharmacokinetics |
Absorption: The bioavailability of fasiglitazone (TAK875) in rats after oral administration is 35%–45%; after oral administration of 10 mg/kg, the peak plasma concentration (Cmax) is 1.8 ± 0.2 μg/mL in 1.5 hours. Food intake did not affect Cmax or AUC (change <10%) [1][2]
- Distribution: The volume of distribution (Vd) in rats was 2.1 ± 0.3 L/kg; the drug was distributed in the pancreas (pancreas/plasma concentration ratio 2.3 ± 0.2 2 hours after administration) and had low blood-brain barrier penetration (brain/plasma ratio 0.12 ± 0.02) [1][2] - Metabolism: Faglikpan (TAK875) was mainly metabolized by hepatic CYP3A4 to produce inactive metabolites (M1 and M2); <10% of the dose was metabolized by CYP2D6 [1][2] - Excretion: The elimination half-life (t1/2) in rats was 4.2 ± Within 0.5 hours; within 72 hours, 60%–70% of the dose is excreted in feces (mainly as metabolites), and 20%–25% is excreted in urine (as the original drug and as metabolites) [1][2] |
| Toxicity/Toxicokinetics |
In vitro hepatotoxicity: The IC50 of fasiglitazone (TAK875) on the viability of primary mouse hepatocytes was 45 μM (MTT test), and the IC50 on the viability of HepG2 cells was 62 μM [4] - In vivo hepatotoxicity: In mice, oral administration of fasiglitazone (TAK875) at a dose of 30 mg/kg/day for 14 days caused mild hepatic steatosis; a dose of 100 mg/kg/day caused severe hepatic necrosis and inflammatory cell infiltration. Serum ALT/AST levels were positively correlated with dose (r = 0.92 for ALT) [4] - Plasma protein binding: The plasma protein binding rate of fasiglitazone (TAK875) in human plasma was 98.5% ± 0.5%, and in rat plasma it was 97.8% ± 0.6% [1][2] - No adverse reactions: No significant changes in renal function (creatinine, blood urea nitrogen) or hematological parameters (erythrocytes, white blood cells) were observed in diabetic rats treated with fasiglitazone (TAK875) (up to 10 mg/kg/day for 28 days) [1][2]
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| References |
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| Additional Infomation |
Fasiglifam belongs to the biphenyl class of compounds. Fasiglippa has been used in clinical trials for the treatment of chronic kidney disease, type 2 diabetes, and type 2 diabetes. 1. Fasiglippa (TAK875) is an oral GPR40/FFA1 agonist that enhances insulin secretion in a glucose-dependent manner, avoiding the risk of hypoglycemia (a common side effect of conventional sulfonylureas) [1][2]. 2. Its hypoglycemic mechanism involves the activation of GPR40 on pancreatic β cells, triggering Ca²⁺ influx and cAMP accumulation, thereby promoting insulin granule exocytosis [1][2]. 3. Clinical development of Fasiglippa (TAK875) has been terminated due to dose-dependent liver injury, as confirmed by preclinical studies (literature). 4) Studies have shown that it induces hepatocyte oxidative stress and inflammatory response by upregulating CYP2E1 and pro-inflammatory cytokines [4].
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| Molecular Formula |
C29H32O7S.1/2H2O
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| Molecular Weight |
533.63
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| Exact Mass |
524.186
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| CAS # |
1000413-72-8
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| Related CAS # |
(R)-Fasiglifam;1234474-57-7;Fasiglifam hemihydrate;1374598-80-7
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| PubChem CID |
24857286
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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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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.77 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 25.0 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: ≥ 2.5 mg/mL (4.77 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 25.0 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: ≥ 2.5 mg/mL (4.77 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (4.77 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. Solubility in Formulation 5: 0.5% CMC+0.25% Tween 80 : 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8740 mL | 9.3698 mL | 18.7396 mL | |
| 5 mM | 0.3748 mL | 1.8740 mL | 3.7479 mL | |
| 10 mM | 0.1874 mL | 0.9370 mL | 1.8740 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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