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]
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