MBX-2982

GPR119 agonist,selective and orally-available CAS# 1037792-44-1

MBX-2982

Catalog No. BCC1732----Order now to get a substantial discount!

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Chemical structure

MBX-2982

3D structure

Chemical Properties of MBX-2982

Cas No. 1037792-44-1 SDF Download SDF
PubChem ID 25025505 Appearance Powder
Formula C22H24N8OS M.Wt 448.54
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (111.47 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]-4-[[4-(tetrazol-1-yl)phenoxy]methyl]-1,3-thiazole
SMILES CCC1=CN=C(N=C1)N2CCC(CC2)C3=NC(=CS3)COC4=CC=C(C=C4)N5C=NN=N5
Standard InChIKey NFTMKHWBOINJGM-UHFFFAOYSA-N
Standard InChI InChI=1S/C22H24N8OS/c1-2-16-11-23-22(24-12-16)29-9-7-17(8-10-29)21-26-18(14-32-21)13-31-20-5-3-19(4-6-20)30-15-25-27-28-30/h3-6,11-12,14-15,17H,2,7-10,13H2,1H3
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of MBX-2982

DescriptionMBX-2982 is a selective, orally-available G protein-coupled receptor 119 (GPR119) agonist.In Vitro: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. Likewise, 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].In Vivo: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 in order to examine a direct GPR119 effect, no DPP-IV inhibitor is co-administered in this experiment, but 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].

References:
[1]. Hothersall JD, et al. Sustained wash-resistant receptor activation responses of GPR119 agonists. Eur J Pharmacol. 2015 Sep 5;762:430-42. [2]. Lan H, et al. Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways. Br J Pharmacol. 2012 Apr;165(8):2799-807. [3]. Yang JW, et al. GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J. 2016 Jan;30(1):324-35.

Protocol

Kinase Assay [1]
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 (300g, 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].

Cell Assay [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 (227g, 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].

Animal Administration [2]
Mice[2] C57BL/6 male mice are used. Overnight fasted, 10 week-old male mice (n=20 per group) are given either vehicle (15% polyethylene glycol 400+85% of 23.5% hydroxypropyl-β-cyclodextrin) or MBX-2982 at 10 mg/kg via oral gavage. Half of the animals (n=10 per group) are killed by CO2 asphyxiation 30 min after compound dosing, and blood is collected by cardiac puncture. To preserve active GLP-1, a DPP-IV inhibitor (10 µL per 1 mL of blood) is pre-added to the blood collection tubes and, before the cardiac puncture, the walls of the syringes are rinsed with the DPP-IV inhibitor. The other half of the animals (n=10 per group) received a bolus of oral glucose (3 g/kg) 30 min after compound dosing, and are killed for blood collection 10 min after the glucose load. GLP-1 levels in the plasma samples are measured using the active GLP-1 (ver 2) kit.

References:
[1]. Hothersall JD, et al. Sustained wash-resistant receptor activation responses of GPR119 agonists. Eur J Pharmacol. 2015 Sep 5;762:430-42. [2]. Lan H, et al. Agonists at GPR119 mediate secretion of GLP-1 from mouse enteroendocrine cells through glucose-independent pathways. Br J Pharmacol. 2012 Apr;165(8):2799-807. [3]. Yang JW, et al. GPR119: a promising target for nonalcoholic fatty liver disease. FASEB J. 2016 Jan;30(1):324-35.

MBX-2982 Dilution Calculator

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MBX-2982 Molarity Calculator

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Preparing Stock Solutions of MBX-2982

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.2295 mL 11.1473 mL 22.2946 mL 44.5891 mL 55.7364 mL
5 mM 0.4459 mL 2.2295 mL 4.4589 mL 8.9178 mL 11.1473 mL
10 mM 0.2229 mL 1.1147 mL 2.2295 mL 4.4589 mL 5.5736 mL
50 mM 0.0446 mL 0.2229 mL 0.4459 mL 0.8918 mL 1.1147 mL
100 mM 0.0223 mL 0.1115 mL 0.2229 mL 0.4459 mL 0.5574 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on MBX-2982

MBX-2982 is a potential first-in-class treatment for type 2 diabetes that targets G protein-coupled receptor 119 (GPR119), a receptor that interacts with bioactive lipids known to stimulate glucose-dependent insulin secretion. Preclinical data indicate that MBX-2982 is a potent selective orally-active GPR119 agonist that functions through a unique dual mechanism of action. First, it acts directly on the beta cell to increase insulin secretion. In addition, MBX-2982 stimulates release of the incretin GLP-1 from the gut. This dual action is unique and may offer improved glucose homeostasis over existing diabetes therapies, with potential for weight loss and improved islet health.

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References on MBX-2982

Sustained wash-resistant receptor activation responses of GPR119 agonists.[Pubmed:26101059]

Eur J Pharmacol. 2015 Sep 5;762:430-42.

G protein-coupled receptor 119 (GPR119) is involved in regulating metabolic homoeostasis, with GPR119 agonists targeted for the treatment of type-2 diabetes and obesity. Using the endogenous agonist oleoylethanolamide and a number of small molecule synthetic agonists we have investigated the temporal dynamics of receptor signalling. Using both a dynamic luminescence biosensor-based assay and an endpoint cAMP accumulation assay we show that agonist-driven desensitization is not a major regulatory mechanism for GPR119 despite robust activation responses, regardless of the agonist used. Temporal analysis of the cAMP responses demonstrated sustained signalling resistant to washout for some, but not all of the agonists tested. Further analysis indicated that the sustained effects of one synthetic agonist AR-231,453 were consistent with a role for slow dissociation kinetics. In contrast, the sustained responses to MBX-2982 and AZ1 appeared to involve membrane deposition. We also detect wash-resistant responses to AR-231,453 at the level of physiologically relevant responses in an endogenous expression system (GLP-1 secretion in GLUTag cells). In conclusion, our findings indicate that in a recombinant expression system GPR119 activation is sustained, with little evidence of pronounced receptor desensitization, and for some ligands persistent agonist responses continue despite removal of excess agonist. This provides novel understanding of the temporal responses profiles of potential drug candidates targetting GPR119, and highlights the importance of carefully examining the the mechanisms through which GPCRs generate sustained responses.

Effect of GRP119 Receptor Agonist, Compound MBX-2982, on Activity of Human Glucokinase.[Pubmed:28944428]

Bull Exp Biol Med. 2017 Sep;163(5):695-698.

Validation of the method for studies of glucokinase activators by the spectrophotometric method in an in vitro test system is carried out. The advantage of NAD coenzyme vs. thio-NAD is proven. Manifest activation of glucokinase by MBX-2982 compound (GPR119 agonist) in a wide range of concentrations is demonstrated experimentally.

GPR119 agonists: a promising approach for T2DM treatment? A SWOT analysis of GPR119.[Pubmed:24060477]

Drug Discov Today. 2013 Dec;18(23-24):1309-15.

Ever since its advent as a promising therapeutic target for type 2 diabetes mellitus (T2DM), G-protein-coupled receptor 119 (GPR119) has received much interest from the pharmaceutical industry. This interest peaked in June 2010, when Sanofi-Aventis agreed to pay Metabolex (Cymabay Therapeutics) US$375 million for MBX-2982, which was a representative orally active GPR119 agonist. However, Sanofi-Aventis opted to terminate the deal in May 2011 and another leading GPR119 agonist, GSK1292263, had a loss of efficacy during its clinical trial. In this review, I discuss the pros and cons of GPR119 through a strengths, weaknesses, opportunities, and threats (SWOT) analysis and propose development strategies for the eventual success of a GPR119 agonist development program.

APD668, a G protein-coupled receptor 119 agonist improves fat tolerance and attenuates fatty liver in high-trans fat diet induced steatohepatitis model in C57BL/6 mice.[Pubmed:28274625]

Eur J Pharmacol. 2017 Apr 15;801:35-45.

G-protein coupled receptor 119 (GPR119) receptor is a rhodopsin-like, class A Galphas-coupled receptor, predominantly expressed in pancreatic islet cells and intestinal entero-endocrine cells. GPR119 has been emerged as a novel therapeutic target for the treatment of dyslipidemia in type 2 diabetes. In this study, we investigated the effect of APD668, a GPR119 agonist alone and in combination with linagliptin, a DPPIV inhibitor on oral fat tolerance test. Our findings demonstrate that APD668, a GPR119 agonist inhibits the intestinal triglyceride absorption after acute fat load in mice. Single dose administration of APD668 increases incretin secretion and enhances total PYY levels in presence of fat load in mice. We found that, the anti-dyslipidemic action of APD668 was reversed in presence of exendin-3 in oral fat tolerance test. In addition, our results showed that exendin-3 (9-39) failed to block the effect of APD668 on gastric emptying indicating that gastric emptying effects of APD668 are indeed mediated through GPR119 receptor dependent mechanism. Combined administration of APD668 and linagliptin significantly increased plasma active GLP-1 levels in-vivo and showed improvement in fat tolerance. However, APD668 failed to show anti-dyslipidemic activity in tyloxapol-induced hyperlipidemia in mice. Furthermore, we investigated the chronic effects of APD668 on hepatic steatosis in high trans-fat diet fed steatohepatitis model in mice. Oral administration of APD668 in HTF diet fed mice ameliorated hepatic endpoints such as plasma ALT, AST, liver weight and steatosis. These findings suggest that GPR119 agonists may represent a promising therapeutic strategy for the treatment of dyslipidemia and non-alcoholic steatohepatitis.

GPR119: a promising target for nonalcoholic fatty liver disease.[Pubmed:26399788]

FASEB J. 2016 Jan;30(1):324-35.

Nonalcoholic fatty liver disease is associated with metabolic syndrome and has the unique characteristic of excess lipid accumulation in liver. G-protein-coupled receptor 119 (GPR119) is a promising target for type 2 diabetes. However, the role of GPR119 activation in hepatic steatosis and its precise mechanism has not been investigated. In primary cultured hepatocytes from wild-type and GPR119 knockout (KO) mice, expression of lipogenic enzymes was elevated in GPR119 KO hepatocytes. Treatment of hepatocytes and HepG2 cells with GPR119 agonists in phase 2 clinical trials (MBX-2982 [MBX] and GSK1292263) inhibited protein expression of both nuclear and total sterol regulatory element binding protein (SREBP)-1, a key lipogenesis transcription factor. Oral administration of MBX in mice fed a high-fat diet potently inhibited hepatic lipid accumulation and expression levels of SREBP-1 and lipogenesis-related genes, whereas the hepatic antilipogenesis effects of MBX were abolished in GPR119 KO mice. MBX activated AMPK and increased Ser-372 phosphorylation of SREBP-1c, an inhibitory form of SREBP-1c. Moreover, inhibition of AMPK recovered MBX-induced down-regulation of SREBP-1. These findings demonstrate for the first time that the GPR119 ligand alleviates hepatic steatosis by inhibiting SREBP-1-mediated lipogenesis in hepatocytes.

Description

MBX-2982 is a selective, orally-available G protein-coupled receptor 119 (GPR119) agonist.

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