TAK-875

TAK-875 is a potent, selective and orally bioavailable GPR40 (G protein-coupled receptor 40) agonist with an EC₅₀ value of 0.014μM for human GPR40. GPR40 is highly expressed in pancreatic β cells and β cell lines in humans and rodents, and has also been found in multiple regions of the human brain. TAK-875 demonstrates potent plasma hypoglycemic and insulin-promoting effects in oral glucose tolerance tests of female Wistar fat rats with impaired glucose tolerance, and has been selected as a clinical candidate drug for the treatment of diabetes^[1].

In vitro, TAK-875 dose-dependently increased intracellular inositol monophosphate (IP) production and Ca²⁺ levels at 0.1-10µM and 3-30µM in rat insulinoma INS-1 833/15 cells under 1-10mM glucose, and stimulated insulin secretion at 0.001-10µM in the presence of 10mM glucose^[2]. TAK-875 at 6.25-100µM for 72h did not alter glucose-stimulated insulin secretion, insulin content, or caspase-3/7 activity in INS-1 833/15 cells^[2].

In vivo, intravenous administration of TAK-875 at 1mg/kg in rats resulted in a plasma clearance (CL) of 34.16mL/h·kg, a terminal half-life (t₁/₂λ) of 4.7h, and a steady-state volume of distribution (V_d(ss)) of 208.49mL/kg, whereas oral gavage at 3mg/kg resulted in good absorption, with an AUC_0–24h of 65µg·h/mL, a C_max of 5.77µg/mL, and an oral bioavailability of 76%^[1]. TAK-875 (1-10mg/kg; p.o.) significantly improved glucose tolerance and enhanced insulin secretion in type 2 diabetic N-STZ-1.5 rat models^[2]. TAK-875 (10mg/kg; p.o.) significantly increased plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats^[2].

References:
[1] Negoro N, Sasaki S, Mikami S, et al. Discovery of TAK-875: A Potent, Selective, and Orally Bioavailable GPR40 Agonist. ACS Med Chem Lett. 2010;1(6):290-294.
[2] Tsujihata Y, Ito R, Suzuki M, 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 Ther. 2011;339(1):228-237.

TAK-875是一种有效的，高选择性的口服生物利用的GPR40（G蛋白偶联受体40）激动剂，对人GPR40的EC₅₀值为0.014μM。GPR40在人类和啮齿动物的胰腺β细胞和β细胞系中高度表达，并且在人类大脑的多个区域也被发现。TAK-875在糖耐量受损的雌性Wistar脂肪大鼠的口服糖耐量试验中显示出有效的血浆降糖和胰岛素促进作用，已被选为治疗糖尿病的临床候选药物^[1]。

体外实验中，TAK-875在大鼠胰岛素瘤INS-1 833/15细胞中，在1-10mM葡萄糖条件下，于0.1-10µM范围内剂量依赖性促进细胞内肌醇单磷酸酶生成，于3-30µM范围内提高细胞内Ca²⁺浓度；同时，在10mM葡萄糖条件下，于0.001-10µM范围内促进胰岛素分泌^[2]。6.25-100µM TAK-875处理INS-1 833/15细胞72小时，不影响葡萄糖刺激的胰岛素分泌、细胞内胰岛素含量或caspase-3/7活性^[2]。

体内实验中，大鼠静脉给予1mg/kg TAK-875后，其血浆清除率（CL）为34.16mL/h·kg，终末半衰期（t₁/₂λ）为4.7小时，稳态分布容积（Vd(ss)）为208.49mL/kg；而口服灌胃3mg/kg后，表现出良好的吸收，AUC_0–24h为65µg·h/mL，C_max为5.77µg/mL，口服生物利用度为76%^[1]。TAK-875（1-10mg/kg；口服）在2型糖尿病N-STZ-1.5大鼠模型中显著改善葡萄糖耐量并增强胰岛素分泌^[2]。此外，TAK-875（10mg/kg；口服）在雄性Zucker糖尿病肥胖大鼠中显著提高血浆胰岛素水平并降低空腹高血糖^[2]。