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| Targets |
PPARδ (EC50 = 0.4 nM); PPARδ (EC50 = 7.9 nM); PPARδ (EC50 = 10 nM)
MA-0204 specifically targets peroxisome proliferator-activated receptor δ (PPARδ), a nuclear receptor that plays a key role in regulating lipid metabolism, energy homeostasis, and inflammation. It is a highly selective modulator, with an EC50 of 0.4 nM for human PPARδ. Its selectivity is demonstrated by its significantly lower activity at PPARα (EC50 > 6,660 nM), indicating a high degree of specificity for the PPARδ isoform. Upon binding, MA-0204 activates PPARδ, which then functions as a transcription factor to regulate the expression of target genes involved in fatty acid oxidation, such as ANGPTL4, CPT1, and PDHK4. This activation promotes a shift towards oxidative metabolism, which is particularly relevant in tissues with high energy demands, such as skeletal muscle. |
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| ln Vitro |
MA-0204 exhibits a selectivity of >10,000 times for PPARδ activation relative to PPARα and PPARγ receptors. MA-0204 has good permeability, minimal efflux potential, and high protein binding to mouse plasma.[1].
In mice with DMD, MA-0204 (1.2–12 nM) enhances fatty acid oxidation in the muscle myoblasts[1]. In muscle myoblasts from DMD patients, MA-0204 (0.04–40 nM) activates target gene expression[1]. In vitro, MA-0204 is a highly potent and selective PPARδ agonist. It has an EC50 of 0.4 nM for human PPARδ in reporter gene assays using CV-1 cells expressing the human receptor. Its selectivity is further underscored by its EC50 values of 7.9 nM and 10 nM for mouse and rat PPARδ, respectively, indicating cross-species activity. In primary human renal proximal tubule cells, MA-0204 upregulates the expression of FAO genes, resulting in increased mitochondrial fatty acid oxidation. In primary myoblasts from a patient with Duchenne muscular dystrophy, it increases the expression of mRNA encoding ANGPTL4, CPT1, and PDHK4. These findings confirm its mechanism of action and its potential to modulate metabolism in relevant cell types. |
| ln Vivo |
In the muscle, PPARδ (30, 100 mg/kg) increases target gene transcription[1].
In vivo, MA-0204 has demonstrated promising effects in preclinical models. In normal rats undergoing ischemia-reperfusion-induced acute kidney injury (IR-AKI), MA-0204 attenuates the increases of plasma and urinary biomarkers of AKI, improves renal function, mitigates proximal tubular damage, and boosts mitochondrial gene expression. This suggests a renoprotective effect mediated by PPARδ activation. Furthermore, its potential for the treatment of Duchenne Muscular Dystrophy (DMD) is supported by its ability to upregulate FAO genes in patient-derived myoblasts. By enhancing mitochondrial function and fatty acid oxidation, MA-0204 could potentially improve muscle energetics and reduce the pathology associated with DMD. These in vivo findings support its continued investigation as a therapeutic agent for metabolic and muscular disorders. |
| Enzyme Assay |
In vitro enzyme/receptor binding studies for MA-0204 are typically performed using radioligand binding or functional assays. As a PPARδ agonist, its activity is assessed in cell-based reporter gene assays. In these assays, cells are transfected with a construct containing the PPARδ ligand-binding domain fused to a DNA-binding domain and a reporter gene. The cells are then treated with MA-0204, and the reporter gene activity is measured to determine the EC50 for PPARδ activation. This functional assay is a standard method for characterizing the potency and efficacy of nuclear receptor modulators. The compound's selectivity for PPARδ over other PPAR isoforms is confirmed by testing its activity in similar assays using PPARα and PPARγ.
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| Cell Assay |
In vitro cellular assays for MA-0204 are used to study its effects on cellular metabolism. In these experiments, primary human renal proximal tubule cells or myoblasts from DMD patients are treated with the compound, and the expression of FAO genes is measured by qRT-PCR. Additionally, mitochondrial fatty acid oxidation can be directly measured by incubating cells with radiolabeled fatty acids and quantifying the production of CO2 or acid-soluble metabolites. These assays confirm that PPARδ activation by MA-0204 leads to functional changes in cellular metabolism, supporting its potential therapeutic applications in conditions where mitochondrial function is compromised.
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| Animal Protocol |
In vivo animal studies for MA-0204 have been conducted in models of acute kidney injury and Duchenne Muscular Dystrophy. In the IR-AKI model, normal rats undergo ischemia-reperfusion injury to the kidneys, and then receive MA-0204 treatment. Endpoints include measurements of plasma and urinary biomarkers of kidney injury, histological examination of kidney tissue for tubular damage, and analysis of mitochondrial gene expression. In the context of DMD, studies have been performed using patient-derived myoblasts, and future studies could involve the mdx mouse model of DMD. These studies are crucial for evaluating the compound's efficacy and mechanism in a whole-organism context.
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of MA-0204 are characterized by its oral availability. It is a small molecule with a molecular weight of 476.49 g/mol and a molecular formula of C25H27F3N2O4. Its chemical name is (R)-3-methyl-6-(2-((5-methyl-2-(4-(trifluoromethoxy)phenyl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid. The presence of the trifluoromethoxy group and the overall structure contribute to its lipophilic nature, which is typical for nuclear receptor ligands. As an orally available compound, it is suitable for in vivo administration in preclinical studies. Specific data on its half-life, bioavailability, and metabolism are not detailed in the provided sources but would be essential for its development as a therapeutic agent.
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| Toxicity/Toxicokinetics |
Toxicological data for MA-0204 are limited, as it is a research compound. Its primary value is as a tool for studying PPARδ biology. While specific toxicity profiles are not detailed, its mechanism of modulating a nuclear receptor involved in metabolism could have significant physiological effects. For instance, PPARδ activation has been associated with both beneficial and adverse effects depending on the context. Comprehensive safety studies, including acute and chronic toxicity, genotoxicity, and carcinogenicity, would be required for its development as a therapeutic agent. As with all research chemicals, it should be handled with appropriate laboratory safety precautions.
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| References | |
| Additional Infomation |
MA-0204 is a research-use-only compound that acts as a highly potent and selective PPARδ modulator. Its CAS number is 2095128-17-7. It has been studied for its potential in treating Duchenne Muscular Dystrophy (DMD) and for its renoprotective effects in acute kidney injury. By activating PPARδ and upregulating fatty acid oxidation, it aims to improve mitochondrial function and energy metabolism in affected tissues. It is not an approved drug and is intended for non-clinical research applications.
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| Molecular Formula |
C25H27F3N2O4
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| Molecular Weight |
476.488097429276
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| Exact Mass |
476.192
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| Elemental Analysis |
C, 63.02; H, 5.71; F, 11.96; N, 5.88; O, 13.43
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| CAS # |
2095128-17-7
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| Related CAS # |
2095128-30-4;2095128-17-7 (free acid);
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| PubChem CID |
126752361
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| Appearance |
White to off-white solid powder
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| LogP |
5.8
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
11
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| Heavy Atom Count |
34
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| Complexity |
628
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=CN=C(N1CC2=CC=CC=C2OCCC[C@@H](C)CC(=O)O)C3=CC=C(C=C3)OC(F)(F)F
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| InChi Key |
GYNMVDMBFKGCCR-QGZVFWFLSA-N
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| InChi Code |
InChI=1S/C25H27F3N2O4/c1-17(14-23(31)32)6-5-13-33-22-8-4-3-7-20(22)16-30-18(2)15-29-24(30)19-9-11-21(12-10-19)34-25(26,27)28/h3-4,7-12,15,17H,5-6,13-14,16H2,1-2H3,(H,31,32)/t17-/m1/s1
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| Chemical Name |
(3R)-3-methyl-6-[2-[[5-methyl-2-[4-(trifluoromethoxy)phenyl]imidazol-1-yl]methyl]phenoxy]hexanoic acid
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| Synonyms |
MA 0204MA-0204 MA0204.
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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) |
DMSO: ~43.3 mg/mL (~90.9 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.17 mg/mL (4.55 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (4.55 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 21.7 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 | 2.0987 mL | 10.4934 mL | 20.9868 mL | |
| 5 mM | 0.4197 mL | 2.0987 mL | 4.1974 mL | |
| 10 mM | 0.2099 mL | 1.0493 mL | 2.0987 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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