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Purity: ≥98%
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.
| Targets |
AMPK (EC50 = 8 nM)
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]. |
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| 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].
MK-3903 demonstrated low permeability (Papp = 6 x 10⁻⁶ cm/s) in a bidirectional Lilly laboratories porcine kidney (LLC-PK1) cell model. It is a substrate of human liver uptake transporters OATP1B1 and OATP1B3. It did not exhibit time-dependent inhibition of CYP3A4 activity. In an in vitro human pregnane X receptor (hPXR) assay, it had an EC₅₀ > 30 µM, suggesting it is not a potent PXR agonist. [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].
In diet-induced obese (DIO) mice treated with MK-3903 (30 mg/kg, BID, po) for 15 days, the phosphorylated ACC to total ACC (pACC/ACC) ratio, a marker of AMPK activation, was significantly increased in liver (3.1-fold) and skeletal muscle (1.6-fold) 2 hours after the final dose. [1] Acute oral administration of MK-3903 (3, 10, and 30 mg/kg) to high-fructose fed db/+ mice significantly inhibited hepatic fatty acid synthesis (FAS) at all doses measured 2 and 8 hours post-dose. Inhibition at 2 hours was 60%, 61%, and 66% for 3, 10, and 30 mg/kg, respectively. At 8 hours, inhibition was 29%, 37%, and 49% at the respective doses. [1] Chronic administration of MK-3903 (3-30 mg/kg BID and 30 mg/kg QD, po) for 12 days to DIO mice resulted in a dose-dependent reduction in the insulin resistance index (IRI) during an oral glucose tolerance test (OGTT), primarily driven by suppression of insulin excursion. Significant effects on IRI were observed at 10 mg/kg BID and 30 mg/kg QD without significant body weight change. A modest body weight loss (3.1%) was observed at 30 mg/kg BID. [1] Intraperitoneal administration of an earlier analog, compound 36 (30 mg/kg), led to ~40% inhibition of de novo lipogenesis (DNL) in 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].
AMPK activity was assessed by measuring the phosphorylation of a synthetic peptide substrate (SAMS) by recombinant human AMPK complexes. The specific complex pAMPK7 (α2β1γ1) was pre-activated by phosphorylation of the catalytic α subunit. The allosteric activator AMP served as a positive control for maximal activation. Test compounds were incubated with the enzyme and substrate, and activity was measured. Dose-response curves were generated using 10-point titrations to determine EC₅₀ values and maximum activation percentages relative to AMP. [1] Activation profiling was extended to all 12 recombinant human pAMPK complexes using similar assay conditions to determine isoform selectivity. [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].
For chronic target engagement studies in diet-induced obese (DIO) mice, MK-3903 was administered orally at 30 mg/kg twice daily (BID) for 15 days. Animals were fasted for 4 hours prior to tissue collection. Liver and skeletal muscle were harvested 2 hours after the final dose for analysis of pACC/ACC ratios. [1] For acute effects on hepatic fatty acid synthesis, high-fructose fed db/+ mice were administered MK-3903 orally at single doses of 3, 10, or 30 mg/kg. Hepatic fatty acid synthesis was measured 2 and 8 hours after dosing. [1] For chronic insulin sensitization studies, DIO mice were treated with MK-3903 orally at doses of 3, 10, or 30 mg/kg BID, or 30 mg/kg once daily (QD), for 12 days. Following a 4-hour fast on day 12, an oral glucose tolerance test (OGTT) was performed. Blood glucose and insulin levels were measured 20 minutes after glucose administration to calculate an insulin resistance index (IRI). [1] Pharmacokinetic studies were conducted in C57BL/6 mice, Sprague-Dawley rats, and beagle dogs. For mice, MK-3903 was administered intravenously at 2 mg/kg and orally at 10 mg/kg. Blood samples were collected at various time points to determine plasma concentration. [1] |
| ADME/Pharmacokinetics |
In C57BL/6 mice, MK-3903 exhibited moderate plasma clearance (CLp = 6.8 mL/min/kg), a steady-state volume of distribution (Vdss) of 0.7 L/kg, and a terminal half-life (t1/2) of 2.1 h. The oral bioavailability (F) was 8.4%, and the peak plasma concentration (Cmax) at 1 hour was 2.0 µM. [1] In Sprague-Dawley rats, the CLp was 5.0 mL/min/kg, the Vdss was 0.6 L/kg, the t1/2 was 1.7 h, and the oral bioavailability was 25% (4 mg/kg dose, Cmax = 4.8 µM, tmax = 0.5 h). [1]
In beagle dogs, the plasma clearance (CLp) was 13 mL/min/kg, the steady-state volume of distribution (Vdss) was 1.1 L/kg, the half-life (t1/2) was 2.4 h, and the oral bioavailability (F) was 78% (1 mg/kg dose, Cmax = 1.1 µM, tmax = 0.5 h). [1] Early analog compound 36 had a high plasma clearance (60 mL/min/kg) and low oral bioavailability (7%) in wild-type mice. In BCRP (ABCG2) knockout mice, the clearance was significantly reduced (approximately 30-fold to 2.9 mL/min/kg), and the bioavailability was significantly increased (approximately 10-fold to 77%), indicating that it is a BCRP substrate. [1] |
| Toxicity/Toxicokinetics |
MK-3903 is a weak, reversible inhibitor of CYP3A4 and CYP2D6 (apparent IC₅₀ > 50 µM) and does not cause time-dependent inhibition of CYP3A4. [1] It has moderate binding to the prostaglandin DP2 receptor (IC₅₀ = 1.8 µM), but this binding is negligible in the presence of serum. [1] In kinase profile screening, it showed inhibitory activity against p38-regulated/activated protein kinase (PRAK) with an IC₅₀ < 10 µM. [1] In the described mouse studies, no significant toxicity or lethality was observed at the test dose (maximum 30 mg/kg, twice daily for 15 days). A slight decrease in body weight (3.1%) was observed at the highest dosing frequency (30 mg/kg, twice daily). [1]
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| References | |
| Additional Infomation |
MK-3903 was discovered through a lead compound optimization strategy that used a benzimidazole fragment lead compound (compound 4, EC₅₀ = 36 µM) identified from a biochemical database as the starting material. Key optimizations included the introduction of a thioaryl acid linker at the 2-position of the benzimidazole core, the introduction of a hydrophobic biphenyl group at the 5-position, and the subsequent replacement of the sulfur atom in the linker with an oxygen atom. These optimizations together improved the potency of the compound by about four orders of magnitude. [1] AMPK activation is expected to improve metabolic parameters in type 2 diabetes by inhibiting fatty acid synthesis and gluconeogenesis in the liver, while stimulating fatty acid oxidation and glucose uptake in muscles. [1] Based on encouraging preclinical results in mouse models, including target binding, improved lipid metabolism, and enhanced insulin sensitivity, MK-3903 has been designated as a candidate drug for this type of AMPK activator for further research. [1]
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| Molecular Formula |
C27H19CLN2O3
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| Molecular Weight |
454.904365777969
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| Exact Mass |
454.108
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| Elemental Analysis |
C, 71.29; H, 4.21; Cl, 7.79; N, 6.16; O, 10.55
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| CAS # |
1219737-12-8
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| Related CAS # |
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| PubChem CID |
45256689
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| Appearance |
White to off-white solid powder
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| LogP |
7.1
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
33
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| Complexity |
664
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
FIKQZQDYGXAUHC-UHFFFAOYSA-N
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| 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)
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| Chemical Name |
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: ≥90 mg/mL
Water: <1mg/mL Ethanol: <1mg/mL |
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| 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.
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.
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