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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).
Physicochemical Properties
| Molecular Formula | C29H32O7S.1/2H2O | |
| Molecular Weight | 533.63 | |
| Exact Mass | 524.186 | |
| CAS # | 1000413-72-8 | |
| Related CAS # | (R)-Fasiglifam;1234474-57-7;Fasiglifam hemihydrate;1374598-80-7 | |
| PubChem CID | 24857286 | |
| Appearance | White to off-white solid powder | |
| Density | 1.3±0.1 g/cm3 | |
| Boiling Point | 739.1±60.0 °C at 760 mmHg | |
| Flash Point | 400.8±32.9 °C | |
| Vapour Pressure | 0.0±2.6 mmHg at 25°C | |
| Index of Refraction | 1.587 | |
| LogP | 4.36 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 11 | |
| Heavy Atom Count | 37 | |
| Complexity | 828 | |
| Defined Atom Stereocenter Count | 1 | |
| Synonyms |
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| HS Tariff Code | 2934.99.9001 | |
| 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) |
Biological Activity
| 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]. | ||
| 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]. | ||
| Animal Protocol |
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| References |
[1]. 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. [2]. 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]. 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. [4]. 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. |
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| Additional Infomation |
Fasiglifam is a member of biphenyls. Fasiglifam has been used in trials studying the treatment of Chronic Kidney Disease, Type 2 Diabetes Mellitus, and Diabetes Mellitus, Type 2. |
Solubility Data
| 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. 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. 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 corn oil and mix evenly. 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 (Please use freshly prepared in vivo formulations for optimal results.) |
| 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 |