生物活性

• 描述GPR40 is one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, which mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. TAK-875 is a potent, selective, and orally bioavailable anago-allosteric modulator of hGPR40 with EC50 value of 14nM in a FLIPR assay. TAK-875 can stimulate glucose-dependent insulin secretion, making it act in a unique mode for the treatment of type-2 diabetes mellitus. Single oral dosing of TAK-875 at dose of 3mg/kg, at 1h prior to the oral glucose challenge, reduced the blood glucose excursion and augmented insulin secretion in female Wistar fatty rats. Six-week treatment with combination of TAK-875 (10 mg/kg, b.i.d.) with metformin (50 mg·kg−1, q.d.) significantly potentiate their effect alone on decrease of glycosylated Hb and increase in fasting plasma insulin levels, as well as maintained pancreatic insulin content to the same level compared with normal rats without affecting pancreatic glucagon content in Zucker diabetic fatty rats.
• 作用机制TAK-875 can interact with GPR40 directly through three groups of interactions and form a complex is in an inactive-like state.^[1][2]

• 动物研究
  剂量	Rat: 3 mg/kg - 30 mg/kg[4] (p.o.), 1000 mg/kg[5] (p.o.)
  给药途径	p.o.

• 临床研究

• NCT号	适应症或疾病	临床期	招募状态	预计完成时间	地点
  NCT01433393	Diabetes Mellitus	Phase 3	Completed	-	Japan ... more >> Kisarazu-shi, Chiba, Japan Matsuyama-shi, Ehime, Japan Fukuoka-shi Nishi-ku, Fukuoka, Japan Kasuga-shi, Fukuoka, Japan Naka-shi, Ibaragi, Japan Tsuchiura-shi, Ibaragi, Japan Takamatsu-shi, Kagawa, Japan Kyoto-shi Fushimi-ku, Kyoto, Japan Nagasaki-shi, Nagasaki, Japan Kashihara-shi, Nara, Japan Kashiwara-shi, Osaka, Japan Osaka-shi Tsurumi-ku, Osaka, Japan Sakai-shi Nishi-ku, Osaka, Japan Shimotsuke-shi, Tochigi, Japan Chiyoda-ku, Tokyo, Japan Itabashi-ku, Tokyo, Japan Ota-ku, Tokyo, Japan Shinjuku-ku, Tokyo, Japan Toshima-ku, Tokyo, Japan Collapse <<
  NCT01585792	Diabetic Patients	Phase 3	Completed	-	Japan ... more >> Fukuoka-shi, Fukuoka, Japan Sumida-ku, Tokyo, Japan Collapse <<
  NCT01007097	Diabetes Mellitus, Type 2	Phase 2	Completed	-	-

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• 参考文献

• [1] Negoro N, Sasaki S, et al. Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett. 2010 Jun 18;1(6):290-4.

  [2] Srivastava A, Yano J, et al. High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875. Nature. 2014 Sep 4;513(7516):124-7.

  [3] Ito R, Tsujihata Y, et al. TAK-875, a GPR40/FFAR1 agonist, in combination with metformin prevents progression of diabetes and β-cell dysfunction in Zucker diabetic fatty rats. Br J Pharmacol. 2013 Oct;170(3):568-80.