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| Targets |
ZLN024 targets AMP-activated protein kinase (AMPK), a key regulator of cellular energy homeostasis. As an allosteric activator, it binds to AMPK and enhances its activity without increasing the ADP/ATP ratio. It activates α1β1γ1 and α2β1γ1 AMPK heterotrimers with EC₅₀ values of 0.42 and 0.95 µM, respectively. By activating AMPK, ZLN024 stimulates glucose uptake and fatty acid oxidation in muscle cells and decreases fatty acid synthesis and glucose output in hepatocytes. This makes it a valuable tool for studying AMPK signaling and its role in metabolism and disease.
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| ln Vitro |
ZLN024 allosterically promotes the active AMPK heterotrimer and the inactive α1 subunit truncations α1 (1-394) and α1 (1-335), but not α1 (1-312). Activation of AMPK by ZLN024 requires prephosphorylation of Thr-172 by at least one upstream kinase and protects AMPK Thr-172 from dephosphorylation by PP2Cα. ZLN024 activates AMPK in L6 myotubes, promoting glucose uptake and fatty acid oxidation without altering the ADP/ATP ratio. Random screening of AMPK α1β1γ1 heterotrimers utilizing the established scintillation proximity assay (SPA) assay found a novel AMPK activator, ZLN024. ZLN024 directly activates recombinant AMPK α1β1γ1 and its homologue α2β1γ1 in a concentration-dependent manner. ZLN024 raises the activity of α1β1γ1 by 1.5-fold with an EC50 of 0.42 µM and increases the activity of α2β1γ1 by 1.7-fold with an EC50 of 0.95 µM. ZLN024 also directly activates recombinant AMPK α1β2γ1, with an activation effect of 1.7-fold and an EC50 of 1.1 µM; AMPK α2β2γ1 increases by 1.6-fold with an EC50 of 0.13 µM [1].
In vitro, ZLN024 activates AMPK in L6 myotubes and stimulates glucose uptake and fatty acid oxidation without increasing the ADP/ATP ratio. In primary hepatocytes, it decreases fatty acid synthesis and glucose output. Its activity is typically assessed by measuring AMPK phosphorylation and activity in cell lysates using Western blotting or kinase activity assays. Glucose uptake is measured using radiolabeled glucose or fluorescent glucose analogues. Fatty acid oxidation is measured by the oxidation of radiolabeled fatty acids. These assays provide quantitative data on the compound's effects on cellular metabolism. |
| ln Vivo |
For five weeks, C57BKS db/db mice were given ZLN024 at a dose of 15 mg/kg/day by gavage; metformin (Met) at a dose of 250 mg/kg/day served as a positive control. When compared to the vehicle group, food consumption and body weight did not alter significantly during the course of treatment. After four weeks of treatment, ZLN024 enhanced glucose tolerance. ZLN024 15% lowers blood glucose during fasting. Triacylglycerol, total cholesterol, and liver tissue weight are all decreased [1].
In vivo, ZLN024 reduces liver triacylglycerol and total cholesterol content and improves glucose tolerance in db/db mice, a model of type 2 diabetes. It reduces glucose intolerance and fatty liver characteristics in diabetic db/db mice. These effects are consistent with its mechanism of action as an AMPK activator. The compound provides a promising therapeutic approach for type 2 diabetes mellitus and metabolic syndrome. Its efficacy in animal models supports further development as a potential therapeutic agent for metabolic disorders. |
| Enzyme Assay |
In vitro non-cell enzyme assays for ZLN024 involve measuring its activation of AMPK using purified AMPK heterotrimers. The compound is incubated with AMPK, ATP, and a peptide substrate, and kinase activity is measured by fluorescence or scintillation counting. EC₅₀ values are calculated from dose-response curves. The compound's binding to AMPK can be assessed using surface plasmon resonance or isothermal titration calorimetry. These assays provide quantitative data on the compound's potency and mechanism of activation.
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| Cell Assay |
In vitro cell-based assays for ZLN024 use L6 myotubes and primary hepatocytes to study its effects on glucose uptake, fatty acid oxidation, and glucose output. Cells are treated with varying concentrations of the compound, and parameters such as glucose uptake (radiolabeled or fluorescent glucose), fatty acid oxidation (radiolabeled fatty acids), and glucose output (glucose production from gluconeogenic substrates) are measured. AMPK phosphorylation and activity are assessed by Western blotting or kinase activity assays. These studies help to characterize the compound's cellular mechanism of action.
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| Animal Protocol |
In vivo animal studies for ZLN024 employ db/db mice, a model of type 2 diabetes. The compound is administered orally, and parameters such as blood glucose, glucose tolerance (OGTT), liver triacylglycerol and total cholesterol content, and fatty liver characteristics are assessed. Pharmacokinetic studies in these models provide information about the compound's absorption, distribution, metabolism, and excretion. Its efficacy in reducing glucose intolerance and fatty liver supports its potential as a therapeutic agent for type 2 diabetes and metabolic syndrome.
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| ADME/Pharmacokinetics |
ZLN024 has a molecular weight of 325.22 g/mol and a molecular formula of C₁₃H₁₃BrN₂OS. Its chemical name is 2-[[2-(2-Bromo-4-methylphenoxy)ethyl]thio]-pyrimidine. The compound is soluble in DMSO and should be stored under appropriate conditions, typically at -20°C, protected from light and moisture. Its purity is typically ≥98% by HPLC. Detailed pharmacokinetic parameters such as half-life, volume of distribution, and clearance have not been extensively characterized.
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| Toxicity/Toxicokinetics |
The toxicity profile of ZLN024 has not been comprehensively evaluated in published studies. As a research compound, it is not intended for human therapeutic use without further safety evaluation. Its effects on AMPK activation suggest that it may have significant metabolic effects that require careful evaluation. Standard laboratory safety precautions should be followed when handling the compound.
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| References | |
| Additional Infomation |
ZLN024 is a novel AMPK allosteric activator that activates AMPK heterotrimers with EC₅₀ values of 0.42 and 0.95 µM. It stimulates glucose uptake and fatty acid oxidation and decreases fatty acid synthesis and glucose output. ZLN024 reduces liver triacylglycerol and total cholesterol content and improves glucose tolerance in db/db mice. It provides a promising therapeutic approach for type 2 diabetes mellitus and metabolic syndrome. Not approved for clinical use; intended for research purposes only.
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| Molecular Formula |
C13H13BRN2OS
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| Molecular Weight |
325.224120855331
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| Exact Mass |
323.993
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| CAS # |
723249-01-2
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| Related CAS # |
ZLN024 hydrochloride;1883548-91-1
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| PubChem CID |
1825716
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
443.3±35.0 °C at 760 mmHg
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| Flash Point |
221.9±25.9 °C
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| Vapour Pressure |
0.0±1.0 mmHg at 25°C
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| Index of Refraction |
1.638
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| LogP |
3.96
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
18
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| Complexity |
239
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC1=CC=C(OCCSC2=NC=CC=N2)C(Br)=C1
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| InChi Key |
KWJRSHZSULRJHE-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C13H13BrN2OS/c1-10-3-4-12(11(14)9-10)17-7-8-18-13-15-5-2-6-16-13/h2-6,9H,7-8H2,1H3
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| Chemical Name |
2-[2-(2-bromo-4-methylphenoxy)ethylsulfanyl]pyrimidine
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0748 mL | 15.3742 mL | 30.7484 mL | |
| 5 mM | 0.6150 mL | 3.0748 mL | 6.1497 mL | |
| 10 mM | 0.3075 mL | 1.5374 mL | 3.0748 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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