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| Targets |
Ki: 2.2 nM (C5a)sup>[1] IC50: 3.1 nM (Ca2+ mobilization,), 2.7 nM (Chemotaxis), and 1.6 nM (ROS)[1]
W54011 targets the C5a receptor (C5aR1/CD88), a G protein-coupled receptor that mediates the inflammatory effects of the complement component C5a. The compound inhibits the binding of 125I-labeled C5a to human neutrophils with a Ki of 2.2 nM. By blocking the C5a receptor, W54011 prevents C5a-induced inflammatory responses, including intracellular Ca²⁺ mobilization, chemotaxis, and reactive oxygen species generation. The compound shows no agonist activity up to 10 µM, indicating that it functions as a pure antagonist rather than a partial agonist. The C5a receptor is involved in various inflammatory and immune processes, and its antagonism has therapeutic potential in conditions such as sepsis, ischemia-reperfusion injury, and inflammatory diseases. W54011's high affinity and specificity for the C5a receptor make it a valuable tool for studying the role of C5a signaling in health and disease. |
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| ln Vitro |
W-54011 is a complete antagonist since it moves the concentration-response curves to the right of C5a without lowering the peak responses in the C5a-induced intracellular Ca2+ mobilization experiment with human neutrophils and does not exhibit agonistic activity at concentrations as high as 10 μM. W-54011 has no effect at concentrations up to 10 μM on Ca2+ mobilization triggered with sub-maximally efficacious quantities of IL-8 (0.1 nM), fMLP (1 nM), and platelet-activating factor (0.3 nM). W-54011 is extremely selective for the C5a receptor, as this data shows[1].
In vitro, W54011 demonstrates potent inhibition of C5a-induced responses in human neutrophils. The compound inhibits the binding of 125I-labeled C5a to human neutrophils with a Ki of 2.2 nM. It inhibits C5a-induced intracellular Ca²⁺ mobilization with an IC₅₀ of 3.1 nM, chemotaxis with an IC₅₀ of 2.7 nM, and reactive superoxide species generation with an IC₅₀ of 1.6 nM. The compound shows no agonist activity up to 10 µM. In studies investigating the role of C5a in glioblastoma, W54011 has been shown to counteract C5a-induced malignancy in GBM tumorspheres. The compound can promote the osteogenic differentiation of dental pulp stem cells in an inflammatory environment in vitro. W54011's potent and selective inhibition of C5a receptor signaling makes it a valuable tool for studying the role of complement in various inflammatory and malignant conditions. |
| ln Vivo |
In male mongolian gerbils, oral administration of W-54011 (3-30 mg/kg) for four hours reduced C5a-induced neutropenia in a dose-dependent manner[1]. In the context of rhC5a-induced intracellular Ca2+ mobilization of neutrophils in different species, the species selectivity of W-54011 is investigated. With IC50 values of 1.7 nM and 3.2 nM, respectively, the W-54011 can block the reaction in cynomolgus monkeys and gerbils, but not in mice, rats, guinea pigs, rabbits, or dogs[1].
In vivo, W54011 demonstrates efficacy in various animal models of inflammation and disease. The compound is orally active and has anti-inflammatory effects. In a rat model, W54011 (10 mg/kg, oral) inhibited C5a agonist-induced paw edema. In glioblastoma studies, in vivo studies using orthotopic xenograft mouse models injected with GBM tumorspheres have shown that inhibition of C5a using W54011 may have therapeutic potential for patients with high C5a expression. Preliminary in vivo data suggest that W54011-loaded Bio-Oss may facilitate the healing of inflammatory mandibular defects. In studies investigating the role of C5a in inflammation, W54011 has been shown to prevent C5a-induced neutropenia in gerbils. The compound's oral bioavailability and in vivo efficacy make it a valuable tool for studying the role of C5a signaling in disease and for validating C5a receptor as a therapeutic target. |
| Enzyme Assay |
In vitro receptor binding assays for W54011 employ radioligand displacement techniques using membrane preparations from human neutrophils or cells expressing the C5a receptor. The assay involves incubating W54011 at varying concentrations with the membrane preparation and a fixed concentration of 125I-labeled recombinant human C5a (125I-rhC5a). Following incubation, bound and free radioligand are separated by rapid filtration through glass fiber filters, and the radioactivity retained on the filters is measured by gamma counting. Non-specific binding is determined in the presence of a high concentration of unlabeled C5a or a C5a receptor antagonist. Binding affinity (Ki) values are calculated from competition curves using nonlinear regression analysis. For functional assays, human neutrophils are isolated from whole blood and stimulated with C5a in the presence or absence of W54011. Intracellular Ca²⁺ mobilization is measured using fluorescent indicators such as Fura-2 or Fluo-4. Chemotaxis is measured using Boyden chambers or similar devices. Reactive oxygen species generation is measured using luminol-based chemiluminescence or DCFH-DA fluorescence.
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| Cell Assay |
In vitro cellular assays for W54011 typically employ human neutrophils or cell lines expressing the C5a receptor. Neutrophils are isolated from whole blood and cultured in appropriate media. Cells are pretreated with W54011 at various concentrations and then stimulated with C5a. Intracellular Ca²⁺ mobilization is measured using fluorescent indicators. Chemotaxis is assessed using Boyden chambers, where cells migrate toward a C5a gradient, and the number of migrated cells is counted. Reactive oxygen species generation is measured using luminol-based chemiluminescence or DCFH-DA fluorescence. In studies investigating the role of C5a in cancer, glioblastoma tumorspheres or other cancer cell lines may be used to assess the effects of W54011 on proliferation, stemness, and invasiveness. Cell viability is assessed using standard assays such as MTT or resazurin reduction. The compound's effects on signaling pathways can be assessed by Western blotting or other methods.
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| Animal Protocol |
Animal/Disease Models: Male mongolian gerbils (6-12 weeks) injected with rhC5a[1]
Doses: 3 mg/kg, 10 mg/kg, 30 mg/kg Route of Administration: Oral administration; for 4 hrs (hours) Experimental Results: Inhibited C5a-induced neutropenia in a dose-dependent manner. In vivo animal experiments for W54011 employ various models of inflammation, disease, and injury. For studies investigating the role of C5a in inflammation, rodents are administered W54011 orally or intravenously, and inflammatory responses are induced by C5a injection or other means. Paw edema is measured using plethysmometry. For glioblastoma studies, orthotopic xenograft mouse models are used, with tumorspheres injected into the brain. Tumor growth, invasion, and stemness are assessed. For studies investigating wound healing, W54011-loaded Bio-Oss is implanted into mandibular defects, and healing is assessed histologically. For neutropenia studies, gerbils are administered W54011 prior to C5a injection, and neutrophil counts are measured. Dosing regimens vary depending on the experimental objectives, with oral administration at 10 mg/kg or intravenous administration at 1 mg/kg being common. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of W54011 are characteristic of an orally active small molecule. The compound is orally bioavailable and has anti-inflammatory effects in vivo. W54011 has a molecular weight of 493.08 and a molecular formula of C₃₀H₃₇ClN₂O₂. Following oral administration, the compound is absorbed from the gastrointestinal tract and distributed throughout the body. The compound's pharmacokinetic profile in terms of absorption, distribution, metabolism, and excretion is consistent with its use as an oral research tool. W54011 has been shown to be orally active in animal models, with efficacy observed at doses of 10 mg/kg. The compound's half-life and bioavailability have not been extensively characterized in the literature, but its oral activity suggests adequate pharmacokinetic properties for in vivo studies. The compound's metabolism and elimination pathways have not been fully elucidated.
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| Toxicity/Toxicokinetics |
The toxicity profile of W54011 has not been extensively characterized in the literature, as the compound is primarily used as a research tool. The compound shows no agonist activity up to 10 µM, indicating that it does not activate the C5a receptor at concentrations up to this level. In animal studies, W54011 has been administered at doses of 10 mg/kg orally and 1 mg/kg intravenously without reports of significant toxicity. The compound's safety in humans has not been established, as it has not been developed for clinical use. As with any research compound, appropriate safety precautions should be taken when handling W54011. The compound's potential for off-target effects or drug-drug interactions has not been extensively studied. The compound is intended for research use only and is not approved for human therapeutic use.
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| References | |
| Additional Infomation |
W54011 is a potent, specific, and orally effective C5a receptor antagonist. It has anti-inflammatory and C5a receptor antagonistic effects.
See also: W54011 (note moved to). W54011 is a potent, specific, and orally active non-peptide C5a receptor (CD88) antagonist with anti-inflammatory effects. It inhibits the binding of 125I-labeled C5a to human neutrophils with a Ki of 2.2 nM. It inhibits C5a-induced intracellular Ca²⁺ mobilization (IC₅₀ = 3.1 nM), chemotaxis (IC₅₀ = 2.7 nM), and reactive superoxide species generation (IC₅₀ = 1.6 nM) in human neutrophils, with no agonist activity up to 10 µM. W54011 has a molecular weight of 493.08 and a molecular formula of C₃₀H₃₇ClN₂O₂. It has anti-inflammatory and C5a receptor antagonistic effects. In vivo, W54011 (10 mg/kg, oral) inhibits C5a agonist-induced paw edema in rats and prevents C5a-induced neutropenia in gerbils. W54011 is a research tool for studying complement-mediated inflammatory diseases and has no approved clinical indications. |
| Molecular Formula |
C30H36N2O2
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|---|---|
| Molecular Weight |
493.07998
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| Exact Mass |
492.254
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| CAS # |
405098-33-1
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| PubChem CID |
5311121
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| Appearance |
White to light yellow solid powder
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| Boiling Point |
619ºC at 760 mmHg
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| Flash Point |
328.2ºC
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| LogP |
7.467
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
35
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| Complexity |
634
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
DVYASSBBADJRAS-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C30H36N2O2/c1-21(2)23-11-16-26(17-12-23)32(20-22-9-14-25(15-10-22)31(3)4)30(33)28-8-6-7-24-13-18-27(34-5)19-29(24)28/h9-19,21,28H,6-8,20H2,1-5H3
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| Chemical Name |
N-[(4-dimethylaminophenyl)methyl]-7-methoxy-N-(4-propan-2-ylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide
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| Synonyms |
W-54011 W 54011 W54011
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 : ≥ 28 mg/mL (~56.79 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.07 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 (5.07 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.07 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0281 mL | 10.1403 mL | 20.2807 mL | |
| 5 mM | 0.4056 mL | 2.0281 mL | 4.0561 mL | |
| 10 mM | 0.2028 mL | 1.0140 mL | 2.0281 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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