| Size | Price | Stock | Qty |
|---|---|---|---|
| 5mg |
|
||
| 10mg |
|
||
| 25mg |
|
||
| 50mg |
|
||
| 100mg |
|
||
| 250mg | |||
| 500mg | |||
| Other Sizes |
| Targets |
MK-0941 specifically targets glucokinase (GK), a hexokinase isozyme (subtype IV) expressed primarily in the liver and pancreatic beta cells. Unlike other hexokinases that are inhibited by their product, GK is not subject to feedback inhibition by glucose-6-phosphate, allowing it to act as a glucose sensor. MK-0941 is an allosteric activator, meaning it binds to a site on the GK enzyme distinct from the active site. This binding induces a conformational change that increases the enzyme's affinity for its substrate, glucose, and enhances its catalytic activity. This mechanism is glucose-dependent; the compound's effect is more pronounced at higher glucose concentrations, which is a key safety feature intended to minimize the risk of hypoglycemia. By activating GK, MK-0941 potentiates GSIS in pancreatic beta cells and promotes glucose utilization and storage in the liver, thereby lowering both fasting and postprandial blood glucose levels.
|
|---|---|
| ln Vitro |
In vitro studies have confirmed that MK-0941 is a potent and selective activator of glucokinase. In enzymatic assays using recombinant human glucokinase, MK-0941 demonstrates EC50 values of 240 nM in the presence of 2.5 mM glucose and 65 nM in the presence of 10 mM glucose. This lower EC50 at higher glucose concentrations confirms its glucose-dependent mechanism of action. The compound is highly selective for glucokinase and does not significantly activate other hexokinase isoforms. These in vitro data provide strong evidence that MK-0941 acts as a direct allosteric activator of GK, potentiating its activity in a glucose-dependent manner. Cellular assays have further shown that MK-0941 can increase insulin secretion from pancreatic beta cells and enhance glucose uptake in hepatocytes, confirming its functional activity in relevant cell types.
|
| ln Vivo |
In vivo, MK-0941 is orally active and has demonstrated anti-diabetic efficacy in preclinical models of type 2 diabetes. Studies in diabetic animal models have shown that oral administration of MK-0941 leads to a significant reduction in blood glucose levels, confirming that its in vitro activity translates to a therapeutic effect in living organisms. The compound has also been evaluated in clinical trials for its potential in treating type 2 diabetes. While it showed efficacy in lowering glucose, its clinical development was likely impacted by an observed increase in the risk of hypoglycemia, as well as elevations in triglycerides and blood pressure. These findings highlight the physiological complexity of GK activation and the challenges in developing safe and effective GKAs.
|
| Enzyme Assay |
The in vitro enzyme/receptor binding assay for MK-0941 involves measuring the activation of recombinant human glucokinase. In this assay, the enzyme is incubated with its substrate, glucose, and ATP in the presence of varying concentrations of MK-0941. The enzymatic activity is measured by quantifying the production of glucose-6-phosphate (G6P) using a coupled enzyme system, often involving G6P dehydrogenase and the reduction of NADP+ to NADPH, which can be monitored spectrophotometrically. The EC50, the concentration required to achieve 50% of the maximal activation, is calculated from dose-response curves. This is the primary assay for characterizing the compound's potency as a glucokinase activator.
|
| Cell Assay |
Cellular assays for MK-0941 are conducted to confirm its functional activity in relevant cell types. For example, its ability to stimulate insulin secretion is assessed in pancreatic beta-cell lines or isolated pancreatic islets. Cells are treated with MK-0941 at various glucose concentrations, and the amount of insulin released into the culture medium is measured by ELISA or radioimmunoassay. Similarly, its effect on glucose uptake can be measured in hepatocyte cell lines using radiolabeled glucose analogs. These cellular assays are crucial for confirming that the enzyme activation observed in biochemical assays translates to functional changes in glucose metabolism and insulin secretion.
|
| Animal Protocol |
In vivo animal experiments for MK-0941 are typically conducted in rodent models of type 2 diabetes, such as the db/db mouse or the Zucker diabetic fatty (ZDF) rat. The compound is administered orally, and its effect on blood glucose levels is monitored over time. Key endpoints include fasting blood glucose, glucose tolerance (assessed by an oral glucose tolerance test), and HbA1c levels. The compound's effect on insulin secretion can also be measured in these models. These in vivo studies are essential for evaluating the therapeutic efficacy of MK-0941 and for assessing its safety profile, including the risk of hypoglycemia.
|
| ADME/Pharmacokinetics |
MK-0941 mesylate has a molecular weight of 556.609 g/mol and a molecular formula of C21H24N4O6S·CH3SO3H. It is a solid and is soluble in DMSO. For storage, it is typically kept at -20°C. It is orally bioavailable, and its mesylate salt form is designed to enhance its solubility and absorption.
|
| Toxicity/Toxicokinetics |
The toxicity profile of MK-0941 has been evaluated in preclinical and clinical studies. A key safety concern for GKAs is the risk of hypoglycemia, and MK-0941 has been associated with this side effect. Additionally, clinical studies have reported elevations in triglycerides and blood pressure. These side effects are significant and have likely been a major factor in the clinical development of the compound. Comprehensive toxicological evaluations would have been conducted as part of its clinical development program.
|
| References |
[2] Comparison of Deconvolution-Based and Absorption Modeling IVIVC for Extended Release Formulations of a BCS III Drug Development Candidate. AAPS J. 2015 Nov;17(6):1492-500. |
| Additional Infomation |
MK-0941 is a potent, orally active, allosteric activator of glucokinase that was developed for the treatment of type 2 diabetes. It acts by increasing the enzyme's affinity for glucose, thereby enhancing insulin secretion and glucose uptake in a glucose-dependent manner. While it demonstrated efficacy in lowering blood glucose, its clinical development has been complicated by an increased risk of hypoglycemia and other metabolic effects like elevated triglycerides and blood pressure. As such, MK-0941 has not received regulatory approval and serves as a valuable research tool for understanding the complex biology of glucokinase activation and its therapeutic potential and limitations in diabetes management.
|
| Molecular Formula |
C22H28N4O9S2
|
|---|---|
| Molecular Weight |
556.60912322998
|
| Exact Mass |
556.13
|
| CAS # |
1137916-97-2
|
| Related CAS # |
MK-0941 free base;752240-01-0
|
| PubChem CID |
25235800
|
| Appearance |
Light yellow to yellow solid powder
|
| LogP |
4.151
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
11
|
| Rotatable Bond Count |
9
|
| Heavy Atom Count |
37
|
| Complexity |
810
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
CCS(=O)(=O)C1=NC=C(C=C1)OC2=CC(=CC(=C2)C(=O)NC3=NN(C=C3)C)O[C@@H](C)CO.CS(=O)(=O)O
|
| InChi Key |
PIDNRTWDGDJKSQ-UQKRIMTDSA-N
|
| InChi Code |
InChI=1S/C21H24N4O6S.CH4O3S/c1-4-32(28,29)20-6-5-16(12-22-20)31-18-10-15(9-17(11-18)30-14(2)13-26)21(27)23-19-7-8-25(3)24-191-5(2,3)4/h5-12,14,26H,4,13H2,1-3H3,(H,23,24,27)1H3,(H,2,3,4)/t14-/m0./s1
|
| Chemical Name |
3-((6-(ethylsulfonyl)-3-pyridinyl)oxy)-5-((1S)-2-hydroxy-1-methylethoxy)-N-(1-methyl-1H-pyrazol-3-yl)benzamide
mesylate
|
| Synonyms |
MK-0941 MK 0941 MK0941 MK-0941 mesylate.
|
| HS Tariff Code |
2934.99.9001
|
| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
|
| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~179.66 mM)
|
|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.17 mg/mL (3.90 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.17 mg/mL (3.90 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 21.7 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.17 mg/mL (3.90 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7966 mL | 8.9830 mL | 17.9659 mL | |
| 5 mM | 0.3593 mL | 1.7966 mL | 3.5932 mL | |
| 10 mM | 0.1797 mL | 0.8983 mL | 1.7966 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Products are for research use only; We do not sell to patients
Copyright 2020 InvivoChem LLC | All Rights Reserved
