TAK-875

GPR40 agonist CAS# 1000413-72-8

TAK-875

Catalog No. BCC3702----Order now to get a substantial discount!

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Chemical structure

TAK-875

3D structure

Chemical Properties of TAK-875

Cas No. 1000413-72-8 SDF Download SDF
PubChem ID 24857286 Appearance Powder
Formula C29H32O7S M.Wt 524.64
Type of Compound N/A Storage Desiccate at -20°C
Synonyms Fasiglifam
Solubility DMSO : ≥ 128 mg/mL (243.98 mM)
*"≥" means soluble, but saturation unknown.
Chemical Name 2-[(3S)-6-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid
SMILES CC1=CC(=CC(=C1C2=CC(=CC=C2)COC3=CC4=C(C=C3)C(CO4)CC(=O)O)C)OCCCS(=O)(=O)C
Standard InChIKey BZCALJIHZVNMGJ-HSZRJFAPSA-N
Standard InChI InChI=1S/C29H32O7S/c1-19-12-25(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/h4,6-9,12-14,16,23H,5,10-11,15,17-18H2,1-3H3,(H,30,31)/t23-/m1/s1
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of TAK-875

DescriptionTAK-875 is a selective agonist of GPR40 with EC50 of 14 nM, 400-fold more potent than oleic acid.
TargetsGPR40    
IC5014 nM (EC50)     

Protocol

Kinase Assay [1]
INS-1 832/13 cells are suspended in RPMI medium containing 11 mM glucose and the supplements described above. These cells are seeded at a density of 2×104 cells/well in a 96-well black plate coated with poly-D-lysine, 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) is added to the plate with 1% BSA and 0.1% DMSO, followed by culture for 72 h. After the culture, caspase 3/7 activity is measured with the Apo-one homogeneous caspase 3/7 assay according to the manufacturer's instructions. Fluorescence intensity is measured at an excitation of 485 nm and an emission at 535 nm.

Cell Assay [1]
INS-1 832/13 cells are suspended in RPMI medium and seeded in a 96-well plate at a density of 2×104 cells/well; 1% BSA and 0.1% DMSO alone (control), palmitic acid (10, 100, and 1000 μM), oleic acid (10, 100, and 1000 μM), or TAK-875 (1, 10, and 100 μM) is added to the plate. After 72-h culture, medium is discarded, and cells are preincubated for 2 h with KRBH containing 1 mM glucose and 0.2% BSA at 37°C. After discarding of the preincubation buffer, KRBH containing 1 or 20 mM glucose and 0.2% BSA is added, and the plate is further incubated for 2 h. The insulin concentration in the supernatant is measured as described above. To measure intracellular insulin content, INS-1 832/13 cells are exposed to 1% BSA and 0.1% DMSO alone (control), palmitic acid (1000 μM), oleic acid (1000 μM), or TAK-875 (100 μM) with 1% BSA and 0.1% DMSO. After incubation, cells are washed once with phosphate-buffered saline, and acid-ethanol solution is added to each well, followed by sonication on ice. Intracellular insulin is extracted by overnight incubation at −30°C, followed by separation of supernatant by centrifugation at 12,000 rpm×5 min at 4°C.

Animal Administration [1]
At 18 weeks of age, the N-STZ-1.5 rats are fasted overnight and orally given vehicle (0.5% methylcellulose) or TAK-875 (1, 3, and 10 mg/kg). Sixty minutes later, all animals receive an oral glucose load (1 g/kg). Blood samples are collected from the tail vein before drug administration, before glucose load (time 0), and 10, 30, 60, and 120 min after the glucose load. Plasma glucose and insulin levels are measured with an AutoAnalyzer 7080 and radioimmunoassay, respectively. To see the effects of TAK-875 on fasting normoglycemia and hyperglycemia, SD rats (8 weeks old) or ZDF and ZL rats (12 weeks old) are fasted overnight and orally given vehicle (0.5% methylcellulose), TAK-875 (10 or 30 mg/kg), nateglinide (50 mg/kg), or glibenclamide (10 mg/kg). Blood samples are collected from the tail vein before drug administration (time 0) and 0.5, 1, 2, and 3 h (SD rats) and 0.5, 1, 2, 4, and 6 h (ZDF and ZL rats) after drug administration, and plasma glucose and insulin levels are measured as described above.

References:
[1]. 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.J Pharmacol Exp [2]. Yoshiyuki Tsujihata, et al. 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]. Nagatake T, et al. 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.

TAK-875 Dilution Calculator

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TAK-875 Molarity Calculator

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Preparing Stock Solutions of TAK-875

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 1.9061 mL 9.5303 mL 19.0607 mL 38.1214 mL 47.6517 mL
5 mM 0.3812 mL 1.9061 mL 3.8121 mL 7.6243 mL 9.5303 mL
10 mM 0.1906 mL 0.953 mL 1.9061 mL 3.8121 mL 4.7652 mL
50 mM 0.0381 mL 0.1906 mL 0.3812 mL 0.7624 mL 0.953 mL
100 mM 0.0191 mL 0.0953 mL 0.1906 mL 0.3812 mL 0.4765 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on TAK-875

TAK-875 is a potent, selective, and oral GPR40 agonist. GPR40 is one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediating enhancement of glucose-stimulated insulin secretion by free fatty acids.

In vitro: TAK-875 exhibited potent agonist activity and high binding affinity to the human receptor. In addition, TAK-875 showed excellent agonist potency selectivity for GPR40 receptor over other members of the FFA receptor family (for which EC50>10 μM) [1].

In vivo: TAK-875 showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance [2].

Clinical trial: TAK-875 acts as a glucose-dependent insulinotropic agent with low hypoglycemic risk. Its P K is suitable for once-daily oral administration.

References:
[1] Negoro N, Sasaki S, Mikami S, Ito M, Suzuki M, Tsujihata Y, Ito R, Harada A, Takeuchi K, Suzuki N, Miyazaki J, Santou T, Odani T, Kanzaki N, Funami M, Tanaka T1, Kogame A, Matsunaga S, Yasuma T, Momose Y.  Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett. 2010 Jun 18;1(6):290-4.
[2] Leifke E, Naik H, Wu J, Viswanathan P, Demanno D, Kipnes M, Vakilynejad M.  A multiple-ascending-dose study to evaluate safety, pharmacokinetics, and pharmacodynamics of a novel GPR40 agonist, TAK-875, in subjects with type 2 diabetes. Clin Pharmacol Ther. 2012 Jul;92(1):29-39.

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References on TAK-875

Long-term safety and efficacy of fasiglifam (TAK-875), a G-protein-coupled receptor 40 agonist, as monotherapy and combination therapy in Japanese patients with type 2 diabetes: a 52-week open-label phase III study.[Pubmed:27178047]

Diabetes Obes Metab. 2016 Sep;18(9):925-9.

This multicentre, open-label, phase III study investigated the safety and efficacy of the G-protein-coupled receptor 40 agonist fasiglifam. Japanese patients with type 2 diabetes and inadequate glycaemic control despite diet and/or exercise (n = 282), or despite diet and/or exercise plus one oral antidiabetic agent [sulphonylurea (n = 262), rapid-acting insulin secretagogue (n = 124), alpha-glucosidase inhibitor (n = 141), biguanide (n = 136), thiazolidinedione (n = 139) or dipeptidyl peptidase-4 inhibitor (n = 138)] were randomized to treatment with fasiglifam 25 or 50 mg once daily for 52 weeks. The primary endpoints were safety variables. The overall incidence of treatment-emergent adverse events (TEAEs) was 75.4-85.1% in the 25 mg group and 78.9-89.9% in the 50 mg group; most TEAEs were mild. Hypoglycaemia was negligible with fasiglifam monotherapy and most common with sulphonylurea combination therapy (12.4 and 9.1% for 25 and 50 mg groups, respectively). Abnormal liver-related laboratory values were uncommon. Glycated haemoglobin levels decreased from week 2 in all groups and were maintained to week 52. Although fasiglifam as monotherapy or in combination regimens was well tolerated during long-term treatment, global concerns about liver safety led to termination of its development after study completion.

Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury.[Pubmed:28108665]

Toxicol Sci. 2017 May 1;157(1):50-61.

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs.

Fasiglifam (TAK-875) has dual potentiating mechanisms via Galphaq-GPR40/FFAR1 signaling branches on glucose-dependent insulin secretion.[Pubmed:27433346]

Pharmacol Res Perspect. 2016 Apr 27;4(3):e00237.

Fasiglifam (TAK-875) is a free fatty acid receptor 1 (FFAR1)/G-protein-coupled receptor 40 (GPR40) agonist that improves glycemic control in type 2 diabetes with minimum risk of hypoglycemia. Fasiglifam potentiates glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells glucose dependently, although the precise mechanism underlying the glucose dependency still remains unknown. Here, we investigated key cross-talk between the GSIS pathway and FFAR1 signaling, and Ca(2+) dynamics using mouse insulinoma MIN6 cells. We demonstrated that the glucose-dependent insulinotropic effect of fasiglifam required membrane depolarization and that fasiglifam induced a glucose-dependent increase in intracellular Ca(2+) level and amplification of Ca(2+) oscillations. This differed from the sulfonylurea glimepiride that induced changes in Ca(2+) dynamics glucose independently. Stimulation with cell-permeable analogs of IP3 or diacylglycerol (DAG), downstream second messengers of Galphaq-FFAR1, augmented GSIS similar to fasiglifam, indicating their individual roles in the potentiation of GSIS pathway. Intriguingly, the IP3 analog triggered similar Ca(2+) dynamics to fasiglifam, whereas the DAG analog had no effect. Despite the lack of an effect on Ca(2+) dynamics, the DAG analog elicited synergistic effects on insulin secretion with Ca(2+) influx evoked by an L-type voltage-dependent calcium channel opener that mimics glucose-dependent Ca(2+) dynamics. These results indicate that the Galphaq signaling activated by fasiglifam enhances GSIS pathway via dual potentiating mechanisms in which IP3 amplifies glucose-induced Ca(2+) oscillations and DAG/protein kinase C (PKC) augments downstream secretory mechanisms independent of Ca(2+) oscillations.

Fasiglifam (TAK-875): Mechanistic Investigation and Retrospective Identification of Hazards for Drug Induced Liver Injury.[Pubmed:28206647]

Toxicol Sci. 2018 Jun 1;163(2):374-384.

TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI). Mechanistic studies were conducted to identify potential DILI hazards (covalent binding burden (CVB), hepatic transporter inhibition, mitochondrial toxicity, and liver toxicity in rats) associated with TAK-875. Treatment of hepatocytes with radiolabeled TAK-875 resulted in a CVB of 2.0 mg/day, which is above the threshold of 1 mg/day considered to be a risk for DILI. Covalent binding to hepatocytes was due to formation of a reactive acyl glucuronide (AG) and, possibly, an acyl-CoA thioester intermediate. Formation of TAK-875AG in hepatocytes and/or in vivo was in the order of non-rodents > human (in vitro only) > rat. These data suggest that non-rodents, and presumably humans, form TAK-875AG more efficiently than rats, and that AG-mediated toxicities in rats may only occur at high doses. TAK-875 (1000 mg/kg/day) formed significant amounts of AG metabolite (TAK-875 and TAK-875AG had similar potencies (within 3-fold) for human multi-drug resistant associated protein 2/4 (MRP2/4) and bile salt export pump, but TAK-875AG was exceptionally potent against MRP3 (0.21 muM). Inhibition of MRPs may contribute to liver accumulation of TAK-875AG. TAK-875 also inhibited mitochondrial respiration in HepG2 cells, and mitochondrial Complex 1 and 2 activities in isolated rat mitochondria. In summary, formation of TAK-875AG, and possibly TAK-875CoA in hepatocytes, coupled with inhibition of hepatic transporters and mitochondrial respiration may be key contributors to TAK-875-mediated DILI.

Description

Fasiglifam (TAK-875) is a potent, selective and orally bioavailable GPR40 agonist with EC50 of 72 nM.

Keywords:

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