TAK-875 (Fasiglifam), GPR40 Agonist

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.

Product information

CAS Number: 1374598-80-7

Molecular Weight: 533.63

Formula: C58H66O15S2

Chemical Name: (S)-2-(6-((2', 6'-dimethyl-4'-(3-(methylsulfonyl)propoxy)biphenyl-3-yl)methoxy)-2, 3-dihydrobenzofuran-3-yl)acetic acid hydrate

Smiles: O.CS(=O)(=O)CCCOC1=CC(C)=C(C2=CC(COC3=CC4OC[C@@H](CC(O)=O)C=4C=C3)=CC=C2)C(C)=C1.CS(=O)(=O)CCCOC1=CC(C)=C(C2=CC(COC3=CC4OC[C@@H](CC(O)=O)C=4C=C3)=CC=C2)C(C)=C1

InChiKey: OJXYMYYDAVXPIK-IWKNALKQSA-N

InChi: InChI=1S/2C29H32O7S.H2O/c2*1-19-12-25(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;/h2*4,6-9,12-14,16,23H,5,10-11,15,17-18H2,1-3H3,(H,30,31);1H2/t2*23-;/m11./s1

Technical Data

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

In Vitro:

TAK-875 was used at 1 µM final concentration in various in vitro assays.

In Vivo:

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.

References:

1. 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.
2. 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.
3. Srivastava A, et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. (2014) Nature. 513(7516):124-7.

Products are for research use only. Not for human use.