TAK-875 (Fasiglifam) is the potent, selective and orally bioavailable partial GPR40 agonist with an EC50 ~14 nM. It has binding affinity to the human GPR40 receptor with Ki of 38 nM and the rat GPR40 receptor with Ki of 140 nM. TAK-875 has no agonist potency to other members of the FFA receptor family with EC50 >10 μM. The 2.3 Å resolution co-complex structure of hGPR40-TAK-875 reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. Consistent with the activation of the Gqα-mediated signaling pathway, TAK-875 augments glucose-dependent insulin secretion in pancreatic β cells. Prolonged stimulation of GPR40/FFA1 by TAK-875 does not cause pancreatic β Cell dysfunction or induction of apoptosis. Termination phase III development of TAK-875 (Fasiglifam) for the potential treatment of type-2 diabetes mellitus was announced in 2013 due to concerns about liver safety.
CAS Number: 1374598-80-7
Molecular Weight: 533.63
Chemical Name: (S)-2-(6-((2', 6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)methoxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid hydrate
Appearance: Solid Power.
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: DMSO up to 100 mM
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥360 days if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
TAK-875 was used at 1 µM final concentration in various in vitro assays.
TAK-875 was dosed to female Wistar fatty rats subjected to oral glucose tolerance test via oral gavage at 3 mg/kg one hour before an oral glucose challenge. Formulation is 0.5% CMC/0.25% Tween 80 in water. In type 2 diabetic N-STZ-1.5 rats, administration of TAK-875 (1-10 mg/kg PO) shows a clear improvement in glucose tolerance and augments insulin secretion. TAK-875 (10 mg/kg, PO) significantly augments plasma insulin levels and reduces fasting hyperglycemia in male Zucker diabetic fatty rats.
- Negoro N, et al. Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. (2010) ACS Med Chem Lett. 1(6):290-4.
- 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. (2011) J Pharmacol Exp Ther. 339(1):228-37.
- Srivastava A, et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. (2014) Nature. 513(7516):124-7.
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