Fasiglifam (TAK-875) Hemihydrate is a novel, orally available, selective GPR40 agonist. TAK-875 exhibits potent agonist activity and high binding affinity to the human GPR40 receptor with Ki of 38 nM. TAK-875 enhanced glucose-induced insulin secretion in a glucose-dependent manner in both human and rat islets. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity. TAK-875 significantly improved glycaemic control in patients with type 2 diabetes with minimum risk of hypoglycaemia.
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Source | Br J Pharmacol (2013). Figure 3. TAK-875 |
| Method | oral | |
| Cell Lines | ZL rats | |
| Concentrations | 3 mg/kg | |
| Incubation Time | 120 min | |
| Results | TAK-875 significantly enhanced insulin secretion before a glucose load (P ≤ 0.01) and tended to augment it at 10 min after glucose load, while metformin showed a trend towards reduce insulin release at 10 min |
| Cell Experiment | |
|---|---|
| Cell lines | INS-1 832/13 cells |
| Preparation method | Measurement of Caspase 3/7 Activity. INS-1 832/13 cells were suspended in RPMI medium containing 11 mM glucose and the supplements described above. These cells were seeded at a density of 2 × 104 cells/well in a 96-well black plate coated with poly-D-lysine (BD BioCoat), and 1% BSA and 0.1% DMSO alone (control), palmitic acid (62.5, 125, 250, 500, and 1000 μM), oleic acid (62.5, 125, 250, 500, and 1000 μM), or TAK-875 (6.25, 12.5, 25, 50, and 100 μM) was added to the plate with 1% BSA and 0.1% DMSO, followed by culture for 72 h. After the culture, caspase 3/7 activity was measured with the Apo-one homogeneous caspase 3/7 assay (Promega, Madison, WI) according to the manufacturer's instructions. Fluorescence intensity was measured at an excitation of 485 nm and an emission at 535 nm. |
| Concentrations | 6.25, 12.5, 25, 50, and 100 μM |
| Incubation time | 72 h |
| Animal Experiment | |
|---|---|
| Animal models | Oral Glucose Tolerance Test and Effects on Fasting Normoglycemia and Hyperglycemia with N-STZ-1.5 rats |
| Formulation | 0.5% methylcellulose |
| Dosages | 10 and 30 mg/kg |
| Administration | oral gavage |
| Molecular Weight | 533.63 |
| Formula | C29H32O7S.1/2H2O |
| CAS Number | 1374598-80-7 |
| Solubility (25°C) | DMSO 90 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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