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MK-3903

Alias: MK3903; MK 3903; MK-3903
Cat No.:V4058 Purity: ≥98%
MK-3903 (MK3903) is a novel, potent and selectiveAMPK (AMP-activated protein kinase)activator with EC50 of 8 nM for α1 β1 γ1 subunit,leading to improved lipid metabolism and insulin sensitization in mice.
MK-3903
MK-3903 Chemical Structure CAS No.: 1219737-12-8
Product category: AMPK
This product is for research use only, not for human use. We do not sell to patients.
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

MK-3903 (MK3903) is a novel, potent and selective AMPK (AMP-activated protein kinase) activator with EC50 of 8 nM for α1 β1 γ1 subunit, leading to improved lipid metabolism and insulin sensitization in mice. It activates 10 of the 12 pAMPK complexes, with maximal activation exceeding 50% and EC50 values in the 8–40 nM range. Following oral administration, MK-3903 demonstrated strong target engagement in the mouse liver, improving lipid metabolism and insulin sensitization in the mice. With less pronounced effects in skeletal muscle, chronic oral administration of MK-3903 significantly increased ACC phosphorylation in the liver. The administration of MK-3903 to various mouse models led to the anticipated changes in lipid metabolism and enhancements in an indicator of insulin sensitization.

Biological Activity I Assay Protocols (From Reference)
Targets
AMPK (EC50 = 8 nM)
ln Vitro
MK-3903 (compound 42) is a potent and selective AMP-activated protein kinase (AMPK) activator with an EC50 of 8 nM. MK-3903 activates 10 of the 12 phosphorylated AMPK (pAMPK) complexes with EC50 values in the range of 8 to 40 nM and maximal activation >50%. MK-3903 does not activate pAMPK6 and only partially activates pAMPK5 (up to 36% maximum). In LLC-PK1 cells, MK-3903 exhibits low permeability (Papp=6 10-6 cm/s), and it is a substrate for the organic anion transporter proteins OATP1B1 and OATP1B3 that are found in human liver uptake transporters. According to the findings, MK-3903 moderately binds to the prostanoid DP2 (CRTH2) receptor (binding IC50=1.8 μM), but not when 10% human serum is present (binding IC50>86 μM)[1].
ln Vivo
MK-3903 (compound 42) exhibits moderate systemic plasma clearance (5.0 to 13 mL/min/kg), a volume of distribution at steady state of 0.6 to 1.1 L/kg, and a terminal halflife of approximately 2 hours in C57BL/6 mice, Sprague to Dawley rats, and beagle dogs. MK-3903 (3, 10, and 30 mg/kg) causes a significant reduction in hepatic fatty acid synthesis (FAS) when administered acutely orally to high-fructose-fed db/+ mice[1].
Enzyme Assay
Enzymatic reaction is carried out. In a nutshell, to produce pAMPK, the target AMPK complex is appropriately diluted in the AMPK reaction buffer and incubated at room temperature for 30 min. After adding appropriately diluted MK-3903 (compound 42) in DMSO (1.2 L total) to the reaction buffer containing pAMPK (15 L per well), the plate is briefly vortexed, and the incubation is then allowed to proceed at room temperature for 30 minutes. After 60 minutes of room temperature incubation, the plate is sealed, and quench buffer is added to stop the reaction. Plots of product vs. activator concentration are used to calculate EC50s and activation parameters[1].
Animal Protocol
In this study, DIO mice that are 17 weeks old are used. Mice are trained to receive vehicle at a dose of 5 mL/kg BID for 5 days (vehicle: 5% Tween 80, 0.25% methylcellulose, 0.02% SDS). At that point, mice are bled, their blood sugar and insulin levels are measured, and the mice are then divided into treatment groups according to body weight, blood sugar, and insulin levels. For a 12-day BID period, MK-3903 (compound 42) is administered orally to each group of animals at doses of 3 mg/kg, 10 mg/kg, 30 mg/kg, or just the vehicle. A second group of mice that received MK-3903 with vehicle at 30 mg/kg for 12 days is also included. Every day, both food intake and body weight are recorded[1].
References

[1]. Hit-to-Lead Optimization and Discovery of 5-((5-([1,1'-Biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic Acid (MK-3903): A Novel Class of Benzimidazole-Based Activators of AMP-Activated Protein Kinase. J Med C

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C27H19CLN2O3
Molecular Weight
454.904365777969
Exact Mass
454.108
Elemental Analysis
C, 71.29; H, 4.21; Cl, 7.79; N, 6.16; O, 10.55
CAS #
1219737-12-8
Related CAS #
1219737-12-8
PubChem CID
45256689
Appearance
White to off-white solid powder
LogP
7.1
Hydrogen Bond Donor Count
2
Hydrogen Bond Acceptor Count
4
Rotatable Bond Count
5
Heavy Atom Count
33
Complexity
664
Defined Atom Stereocenter Count
0
InChi Key
FIKQZQDYGXAUHC-UHFFFAOYSA-N
InChi Code
InChI=1S/C27H19ClN2O3/c1-16-7-12-20(13-21(16)26(31)32)33-27-29-24-14-22(23(28)15-25(24)30-27)19-10-8-18(9-11-19)17-5-3-2-4-6-17/h2-15H,1H3,(H,29,30)(H,31,32)
Chemical Name
5-((5-([1,1′-biphenyl]-4-yl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-methylbenzoic acid
Synonyms
MK3903; MK 3903; MK-3903
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

Shipping Condition
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
Solubility Data
Solubility (In Vitro)
DMSO: ≥90 mg/mL
Water: <1mg/mL
Ethanol: <1mg/mL
Solubility (In Vivo)
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.50 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 25.0 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: ≥ 2.5 mg/mL (5.50 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

 (Please use freshly prepared in vivo formulations for optimal results.)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 2.1983 mL 10.9914 mL 21.9829 mL
5 mM 0.4397 mL 2.1983 mL 4.3966 mL
10 mM 0.2198 mL 1.0991 mL 2.1983 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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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In vivo Formulation Calculator (Clear solution)
Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)
Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)
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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.
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