MBX2982 是口服具有活力的、选择性的 G 蛋白偶联受体 119 (GPR119) 激动剂。

MBX-2982 is a selective, orally-available GPR119 agonist, used for the treatment of diabetes.

In cells pre-treated with MBX-2982 (1 μM) in “chronic incubation/washout” experiments, cAMP accumulation captured by IBMX inclusion is significantly increased compared to control cells (P<0.01; ANOVA; n=3-6) despite extensive washing to remove excess agonist. AR-231,453 produces sustained responses in a similar concentration range to those observed with acute stimulation (a small 1.82 fold shift), with pEC50s of 8.67±0.11 and 8.93±0.17, respectively. In addition, a large but less severe shift in concentration responses (57.54 fold) is observed for MBX-2982 with respective sustained and acute pEC50s of 7.03±0.13 and 8.79±0.12[1].

To examine whether the observations in GLUTag and the primary intestinal cells has physiological relevance, C57BL/6 mice are treated with the GPR119 agonist MBX-2982 at a dose of 10 mg/kg. Note that no DPP-IV inhibitor is co-administered in this experiment to examine a direct GPR119 effect, however, a DPP-IV inhibitor is used to preserve active GLP-1 in the blood samples. The plasma GLP-1 levels from the mice dosed with MBX-2982 are increased without a glucose load, indicating that GPR119-mediated GLP-1 secretion is not dependent on glucose[2].

HEK-GPR119 cells are transfected with GloSensor 22F plasmid and used for dynamic cAMP measurements 24-30 h later. Cell suspensions are made by dislodging the cells using PBS wash and Accutase treatment followed by resuspension in culture media. Cells are then washed twice by pelleting through centrifugation (300 g, 5 min) and resuspension in assay buffer (Hank's Balanced Salt Solution supplemented with 20 mM HEPES and 0.01% fatty acid free BSA, pH 7.4). Cells are then counted and diluted to 600,000 cells/mL in buffer, before GloSensor cAMP reagent is added (2% v/v) and equilibrated with the cells for 2 h at 20°C with periodic mixing. 50 μl/well of cells are added to white-bottomed 384 well plates (30,000 cells/well) in triplicate and baseline luminescence is measuring using an Envision plate-reader. 5 μL of MBX-2982 (serially diluted in DMSO and then diluted 1:100 in assay buffer to obtain ×10 concentrated solution) is manually added to the assay wells to achieve the stated final concentration. Plates are incubated at 20°C with luminescence read at regular intervals to detect dynamic cAMP changes over time within the same wells. cAMP responses at each time-point are expressed as fold over control (vehicle-treated cells)[1].

MBX-2982 is serially diluted in DMSO and then diluted 1:100 in assay buffer to obtain ×10 concentrated solutionis[1]. HEK-GPR119 cells are grown to confluency in flasks, and cell suspensions are made by dislodging cells using PBS wash and accutase treatment followed by resuspension in culture media. Cells are then washed twice by pelleting through centrifugation (227 g, 7 min, 20°C) and resuspension in warm assay buffer (Hank's Balanced Salt Solution supplemented with 20 mM HEPES and 0.01% fatty acid free BSA, pH 7.4), with a 5 min incubation at 37°C after the second wash. Cells are then counted and diluted to 200,000 cells/mL in warm assay buffer[1].

1037792-44-1

C22H24N8OS

448.55

DMSO:10 mM
Powder: -20°C for 3 years
In solvent: -80°C for 2 years