Molecule

Description

TAK-875 is a selective GPR40 agonist with EC50 of 14 nM.

Targets

IC₅₀

In Vitro

TAK-875 exhibits potent agonist activity and high binding affinity to the human GPR40 receptor with K_i of 38 nM. TAK-875 displays weaker affinity toward the rat GPR40 receptor with K_i of 140 nM. TAK-875 displays excellent selectivity, as TAK-875 has little agonist potency to other members of the FFA receptor family with EC50 of >10 μM. ^[1] TAK-875 treatment induces a concentration-dependent increase in intracellular IP production in CHO-hGPR40 with EC50 of 72 nM, more potently than that of endogenous ligand agonist oleic acid which requires much higher ligand concentrations to activate the receptor with EC50 of 29.9 μM. Neither TAK-875 nor oleic acid elicits an IP response in control CHO cells devoid of hGPR40. Consistent with the activation of the Gqα-mediated signaling pathway, TAK-875 augments glucose-dependent insulin secretion in pancreatic β cells. Prolonged stimulation of GPR40/FFA1 by TAK-875 does not cause pancreatic β Cell dysfunction or induction of apoptosis. ^[2]

In Vivo

In a rat model of diabetes, single oral dosing of TAK-875 at 0.3-3 mg/kg reduces the blood glucose excursion and augments insulin secretion during an oral glucose tolerance test, when TAK-875 is administered 1 hour before an oral glucose challenge. ^[1] In type 2 diabetic N-STZ-1.5 rats, administration of TAK-875 (1-10 mg/kg p.o.) shows a clear improvement in glucose tolerance and augments insulin secretion. Additionally, TAK-875 (10 mg/kg, p.o.) significantly augments plasma insulin levels and reduces fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhances insulin secretion nor causes hypoglycemia even at 30 mg/kg. ^[2]

Clinical Trials

A Phase III study of TAK-875 in adults with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease is currently ongoing.

Features

More potent at activating hGPR40 than oleic acid

Ca influx activity of CHO cells expressing human GPR40 (FLIPR assay)

CHO cells stably expressing human GPR40 are plated and incubated overnight in 5% CO₂ at 37 °C. Then, cells are incubated in loading buffer (recording medium containing 2.5 μg/mL fluorescent calcium indicator Fluo 4-AM, 2.5 mM probenecid and 0.1% fatty acid-free BSA) for 60 minutes at 37 oC. Various concentrations of TAK-875 are added into the cells and increase of the intracellular Ca²⁺ concentration after addition is monitored by FLIPR Tsystem for 90 seconds. EC50 value of TAK-875 is obtained with Prism 5 software.

Animal Models

Female Wistar fatty rats subjected to oral glucose tolerance test

Formulation

Formulated in 0.5% methylcellulose

Doses

~3 mg/kg

Administration

Orally