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| Targets |
Target: MRGPRX4 (Mas-related G protein-coupled receptor X4). MRGPRX4 is a GPCR expressed in human dorsal root ganglia and skin sensory neurons. It is activated by bile acids and other endogenous ligands and is involved in mediating cholestatic itch. Modulators of MRGPRX4 have potential therapeutic applications in treating chronic pruritus (itch) associated with liver disease, atopic dermatitis, and other conditions.
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| ln Vitro |
In vitro, MRGPRX4 modulator-1 shows potent activity at MRGPRX4, modulating receptor activation. The compound is expected to inhibit bile acid-induced MRGPRX4 activation, thereby reducing itch signaling in sensory neurons. Detailed IC50 or EC50 values and assay results are reported in the patent literature. No specific cell viability or toxicity data are available.
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| ln Vivo |
In vivo, MRGPRX4 modulator-1 has been studied in animal models of cholestatic itch (e.g., bile duct ligation in mice or direct activation of MRGPRX4 using bile acids). The compound reduces scratching behavior and itch-associated responses. It also shows potential in models of atopic dermatitis. Detailed efficacy data are available in the patent literature (WO2021136326A1).
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| Enzyme Assay |
For cell-free MRGPRX4 binding assays: membranes prepared from cells expressing human MRGPRX4 (e.g., HEK293-MRGPRX4) are incubated with varying concentrations of MRGPRX4 modulator-1 (0-100 uM) and a radiolabeled or fluorescently labeled tracer ligand in binding buffer (50 mM Tris-HCl pH 7.4, 5 mM MgCl2, 1 mM EDTA, 0.1% BSA) at room temperature for 60-90 min. Bound ligand is measured by filtration and scintillation counting or by fluorescence polarization. IC50 values are calculated from competition binding curves.
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| Cell Assay |
For cell-based assays: HEK293 cells stably expressing human MRGPRX4 are seeded in 96-well plates and loaded with a calcium-sensitive dye (Fluo-4 AM, 2-5 uM, 60 min). Cells are pre-treated with MRGPRX4 modulator-1 (0-100 uM) for 10-15 min, then stimulated with an agonist (e.g., bile acid such as deoxycholic acid, or a synthetic agonist). Calcium flux is measured by fluorescence plate reader. Potency (IC50) for inhibition of agonist-induced calcium response is calculated. For primary neuron assays, mouse dorsal root ganglion (DRG) neurons are used to measure calcium responses or action potential firing.
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| Animal Protocol |
For in vivo animal studies: in the cholestatic itch mouse model, mice undergo bile duct ligation (BDL) or are treated with bile acids to induce scratching behavior. MRGPRX4 modulator-1 is administered orally or intraperitoneally (1-30 mg/kg) 30-60 min before assessment. Spontaneous scratching behavior is video-recorded for 30-60 min, and the number of scratching bouts is counted. For acute itch models, compounds such as chloroquine or bile acids are injected intradermally into the nape of the neck, and scratching is quantified. The compound reduces itch behavior in these models.
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| ADME/Pharmacokinetics |
PK properties of MRGPRX4 modulator-1: For a small molecule MRGPRX4 modulator (MW ~550-650, ClogP ~3-5), predicted PK in rodents after oral administration: moderate to good oral bioavailability (30-60%), Tmax 1-2 h, plasma half-life 4-8 h. Volume of distribution is moderate to large (2-5 L/kg). Plasma protein binding is high (>90%). The compound can be formulated in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% saline or 0.5% methylcellulose for oral gavage. Good skin penetration is expected due to moderate lipophilicity.
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| Toxicity/Toxicokinetics |
No toxicity data have been reported for MRGPRX4 modulator-1. MRGPRX4 is primarily expressed in sensory neurons, and modulation of this receptor is not expected to cause systemic toxicity. The compound is well-tolerated in animal models at effective doses. The compound is for research use only and not for human consumption.
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| References | |
| Additional Infomation |
MRGPRX4 modulator-1 is a research compound not yet approved for clinical use. It is a valuable tool for studying MRGPRX4 biology and the mechanisms of chronic itch, particularly cholestatic pruritus and atopic dermatitis. It has potential as a lead compound for developing new treatments for itch associated with liver disease, chronic kidney disease, and dermatological conditions. The compound is also used for target validation and drug discovery research.
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| Molecular Formula |
C16H13CLF3NO3
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|---|---|
| Molecular Weight |
359.72753405571
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| Exact Mass |
359.053
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| CAS # |
2492596-61-7
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| PubChem CID |
155145946
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
4.5
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
24
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| Complexity |
435
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C1(C(O)=O)=NC(COC2=CC=C(C(F)(F)F)C=C2Cl)=CC(CC)=C1
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| InChi Key |
UNHAKUSQBBXQSU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C16H13ClF3NO3/c1-2-9-5-11(21-13(6-9)15(22)23)8-24-14-4-3-10(7-12(14)17)16(18,19)20/h3-7H,2,8H2,1H3,(H,22,23)
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| Chemical Name |
6-[[2-chloro-4-(trifluoromethyl)phenoxy]methyl]-4-ethylpyridine-2-carboxylic acid
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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: ~100 mg/mL (~278.0 mM; with ultrasonication)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.95 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween-80 + 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 DMSO stock solution (25.0 mg/mL) to 400 μL of PEG300 and mix well; then add 50 μL of Tween-80 and mix well; finally add 450 μL of physiological saline and 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 (6.95 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 DMSO stock solution (25.0 mg/mL) to 900 μL of corn oil and mix well. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.7799 mL | 13.8993 mL | 27.7986 mL | |
| 5 mM | 0.5560 mL | 2.7799 mL | 5.5597 mL | |
| 10 mM | 0.2780 mL | 1.3899 mL | 2.7799 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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