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TAK-875 CAS: 1000413-72-8

Category: Inhibitors
Product Name: TAK-875
Cat No: I000065
CAS No: 1000413-72-8
Synonyms: 2-[(3S)-6-[[3-[2,6-dimethyl-4-(3-methylsulfonylpropoxy)phenyl]phenyl]methoxy]-2,3-dihydro-1-benzofuran-3-yl]acetic acid
Molecular Formula: C29H32O7S
Molecular Weight: 524.6
SMILES: CC1=C(C2=CC(COC3=CC=C([C@H](CC(O)=O)CO4)C4=C3)=CC=C2)C(C)=CC(OCCCS(C)(=O)=O)=C1
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
InChIKey: BZCALJIHZVNMGJ-HSZRJFAPSA-N
Solubility: DMSO: ≥ 158 mg/mL
Target: Free fatty acid receptor 1 (FFAR1; GPR40)
IC50: 0.072 μM(EC50)
Storage: Store at -20°C
CAS 1000413-72-8,TAK-875
  • Description

TAK-875(cas 1000413-72-8) is a potent, selective and orally bioavailable GPR40 agonist with EC50 of 0.072 μM.

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. TAK-875 is currently in clinical trials for the treatment of type 2 diabetes mellitus. It was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI).

  • Spec

Appearance:white to off-white solid powder
Purity: > 98%

  • References

1. Toxicol Sci. 2017 Feb 16. doi: 10.1093/toxsci/kfx040. [Epub ahead of print]
Fasiglifam (TAK-875): Mechanistic Investigation and Retrospective Identification of Hazards for Drug Induced Liver Injury.
Otieno MA(1), Snoeys J(2), Lam W(1), Ghosh A(1), Player MR(3), Pocai A(3), Salter R(1), Simic D(1), Skaggs H(1), Singh B(1), Lim HK(1).
Author information:
(1)Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477. (2)Preclinical Development & Safety, Janssen Pharmaceutica NV, Beerse, Antwerpen BE 2340, Belgium. (3)Cardiovascular & Metabolism, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI).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 (≤32.7 μM) in rat liver that was associated with increases in ALT (×4), bilirubin (×9), and bile acids (×3.4), and microscopic findings of hepatocellular hypertrophy and single cell necrosis. 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 μM). 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.
2. J Pharmacol Exp Ther. 2011 Oct;339(1):228-37. doi: 10.1124/jpet.111.183772. Epub 2011 Jul 13.
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.
Tsujihata Y(1), Ito R, Suzuki M, Harada A, Negoro N, Yasuma T, Momose Y, Takeuchi K.
Author information:
(1)Metabolic Disease Drug Discovery Unit,Takeda Pharmaceutical Company Limited, Osaka, Japan. tsujihata_yoshiyuki@takeda.co.jp
G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2, 3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. 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. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. 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 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.
3. ACS Med Chem Lett. 2010 Jun 18;1(6):290-4. doi: 10.1021/ml1000855. eCollection 2010 Sep 9.
Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist.
Negoro N(1), Sasaki S(1), Mikami S(1), Ito M(1), Suzuki M(1), Tsujihata Y(1), Ito R(1), Harada A(1), Takeuchi K(1), Suzuki N(1), Miyazaki J(1), Santou T(1), Odani T(1), Kanzaki N(1), Funami M(1), Tanaka T(1), Kogame A(1), Matsunaga S(1), Yasuma T(1), Momose Y(1).
Author information:
(1)Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 2-17-85, Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2, 3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.


price inquiry for CAS:1000413-72-8, Product:TAK-875