| Size | Price | Stock | Qty |
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| 1mg |
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| 5mg |
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| 10mg |
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| Other Sizes |
| Targets |
CB1R/iNOS[1]
(Rac)-Zevaquenabant is a dual-target inhibitor: it acts as a peripherally restricted antagonist of the cannabinoid receptor type 1 (CB1R) and as an inhibitor of inducible nitric oxide synthase (iNOS). This dual pharmacology is designed to simultaneously block two pathways implicated in the pathogenesis of pulmonary fibrosis and other fibrotic diseases. |
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| ln Vitro |
In vitro activity for the racemic mixture is not detailed. The (S)-enantiomer (Zevaquenabant) is a potent antagonist of CB1R and an inhibitor of iNOS. Its peripheral restriction ensures that it does not cross the blood-brain barrier, thereby avoiding the central side effects associated with brain CB1R antagonism while retaining efficacy in peripheral tissues.
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| ln Vivo |
In vivo, pulmonary delivery of 0.5 mg/kg/day of Zevaquenabant (the active enantiomer) is as effective as systemic delivery of 10 mg/kg/day and matches the efficacy of nintedanib in mitigating bleomycin-induced pulmonary fibrosis (PF) in mice. It reduces infiltrating alveolar macrophages (AMs), particularly pro-fibrotic macrophages, showing target engagement and improved pulmonary functions with reduced collagen deposition.
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| Enzyme Assay |
The binding affinity of Zevaquenabant for CB1R can be determined via a standard radioligand competition binding assay. Membranes from CHO cells expressing human CB1R are incubated with [3H]SR141716A (a selective CB1 antagonist) and varying concentrations of the test compound in assay buffer for 90 min at 30degC. Nonspecific binding is defined with 10 uM unlabeled SR141716A, and bound radioactivity is separated by filtration.
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| Cell Assay |
iNOS inhibitory activity is typically measured using a fluorescence-based assay in cell lysates. RAW 264.7 macrophages are stimulated with lipopolysaccharide (LPS) and interferon-gamma (IFN-gamma) to induce iNOS expression. Cell lysates are then incubated with varying concentrations of Zevaquenabant along with the substrate 4,5-diaminofluorescein diacetate (DAF-2 DA), and the conversion to fluorescent triazolofluorescein is measured to determine the IC50 for iNOS inhibition.
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| Animal Protocol |
An in vivo protocol for pulmonary fibrosis uses the bleomycin-induced model. Male C57BL/6 mice are given a single intratracheal dose of bleomycin to induce fibrosis. Treatment with Zevaquenabant (0.5 mg/kg/day) is administered via pulmonary delivery (e.g., intratracheal instillation or nebulization) starting one day after bleomycin. After 14-21 days, mice are sacrificed for assessment of lung collagen content by Hydroxyproline assay, histological analysis by Masson‘s Trichrome staining, and flow cytometry of alveolar macrophages.
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| ADME/Pharmacokinetics |
Specific PK data for (Rac)-Zevaquenabant is not provided. The active enantiomer is described as a "peripherally restricted" agent, indicating it is designed to have low brain penetration. This peripheral restriction is a key pharmacokinetic property that underlies its safety profile, allowing it to target CB1Rs in the lungs and other organs without causing central side effects.
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| Toxicity/Toxicokinetics |
Zevaquenabant has completed a Phase 1 clinical trial. The peripherally restricted nature of this dual CB1R/iNOS inhibitor is a key safety feature, as it avoids the neuropsychiatric side effects (anxiety, depression, suicidal ideation) observed with brain-penetrant CB1R antagonists. The compound was well-tolerated in pre-clinical models at the efficacious doses.
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| References | |
| Additional Infomation |
Zevaquenabant (S-MRI-1867) is a clinical-stage agent that was developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA). It is notable for its unique dual-targeting of both CB1R and iNOS within a single molecule. The rationale for this dual approach is based on the distinct pathogenic roles of the endocannabinoid system and nitric oxide in pulmonary fibrosis, and the compound has shown promise via local pulmonary delivery as an effective and well-tolerated anti-fibrotic strategy.
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| Molecular Formula |
C25H21CLF3N5O2S
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|---|---|
| Molecular Weight |
547.98
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| Exact Mass |
547.105
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| CAS # |
1610420-28-4
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| Related CAS # |
Zevaquenabant;1998760-00-1
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| PubChem CID |
162640997
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
651.5±65.0 °C at 760 mmHg
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| Flash Point |
347.8±34.3 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.630
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| LogP |
4.65
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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 |
6
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| Heavy Atom Count |
37
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| Complexity |
989
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| Defined Atom Stereocenter Count |
0
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| SMILES |
C/C(=N/C(=N/S(=O)(=O)C1=CC=C(C=C1)C(F)(F)F)/N2CC(C(=N2)C3=CC=C(C=C3)Cl)C4=CC=CC=C4)/N
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| InChi Key |
NLXIJZHFEOSWPU-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H21ClF3N5O2S/c1-16(30)31-24(33-37(35,36)21-13-9-19(10-14-21)25(27,28)29)34-15-22(17-5-3-2-4-6-17)23(32-34)18-7-11-20(26)12-8-18/h2-14,22H,15H2,1H3,(H2,30,31,33)
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| Chemical Name |
(NZ)-N-(1-aminoethylidene)-5-(4-chlorophenyl)-4-phenyl-N'-[4-(trifluoromethyl)phenyl]sulfonyl-3,4-dihydropyrazole-2-carboximidamide
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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: 50 mg/mL (91.24 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (4.56 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 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 (4.56 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 | 1.8249 mL | 9.1244 mL | 18.2488 mL | |
| 5 mM | 0.3650 mL | 1.8249 mL | 3.6498 mL | |
| 10 mM | 0.1825 mL | 0.9124 mL | 1.8249 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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