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| Targets |
CXCR1; CXCR2
CXCR1 and CXCR2 (chemokine receptors). (Rac)-Reparixin is a non-competitive allosteric inhibitor of CXCR1 and CXCR2. It inhibits the binding of interleukin-8 (IL-8/CXCL8) to its receptors, thereby blocking neutrophil chemotaxis and activation. By inhibiting CXCR1/CXCR2 signaling, the compound reduces inflammation and may have anti-tumor effects. The compound's mechanism of action involves binding to an allosteric site on the receptors, preventing receptor activation without directly competing with IL-8 for the orthosteric binding site. |
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| ln Vitro |
Chemokines CXCL8 and CXCL1 play a key role in the recruitment of neutrophils at the site of inflammation. CXCL8 binds two membrane receptors, CXCR1 and CXCR2, whereas CXCL1 is a selective agonist for CXCR2. In the past decade, the physiopathological role of CXCL8 and CXCL1 has been investigated. A novel class of small molecular weight allosteric CXCR1 inhibitors was identified, and reparixin, the first drug candidate, is currently under clinical investigation in the prevention of ischemia/reperfusion injury in organ transplantation. Reparixin binding mode to CXCR1 has been studied and used for a computer-assisted design program of dual allosteric CXCR1 and CXCR2 inhibitors. In this paper, the results of modeling-driven SAR studies for the identification of potent dual inhibitors are discussed, and three new compounds (56, 67, and 79) sharing a common triflate moiety have been selected as potential leads with optimized pharmacokinetic characteristics[5].
(Rac)-Reparixin inhibits the binding of IL-8 to CXCR1 and CXCR2, blocking neutrophil chemotaxis and activation. The compound exhibits anti-inflammatory activity by reducing neutrophil recruitment to sites of inflammation. It may also have anti-tumor effects by inhibiting CXCR1/CXCR2-mediated tumor cell proliferation, migration, and angiogenesis. Its specific in vitro activities depend on the concentrations tested and the assay systems used. The compound has been investigated for its potential in treating inflammatory conditions, ischemia-reperfusion injury, and cancer. |
| ln Vivo |
Pre-treatment with reparixin reduced the motor deficits observed in this model of ischemia and reperfusion. Myeloperoxidase activity and IL-iβ were reduced in the reparixin-treated group. Histological analysis revealed that ischemic injury was also attenuated by reparixin pre-treatment[1].
(Rac)-Reparixin has been investigated in vivo for its anti-inflammatory and anti-tumor effects. The compound reduces neutrophil recruitment and inflammation in animal models of inflammatory diseases. It has also been studied in models of ischemia-reperfusion injury and cancer. The racemic mixture may have different pharmacokinetic and pharmacodynamic properties compared to the individual enantiomers. Further in vivo studies are needed to fully characterize its efficacy and safety profile. |
| Enzyme Assay |
CXCL8 Binding. [125I]CXCL8 [0.2–0.02 nM, specific activity 2,200 Ci/mmol (1 Ci = 37 GBq), Amersham Pharmacia] binding on human PMN or CXCR1/L1.2 transfectants was as described in ref. 11. Saturation experiments were performed on CXCR1/L1.2 transfectants. Nonspecific binding was determined by a 200-fold molar excess of unlabeled CXCL8. Scatchard analysis was performed with the ligand program[2].
The chemokine CXC ligand 8 (CXCL8)/IL-8 and related agonists recruit and activate polymorphonuclear cells by binding the CXC chemokine receptor 1 (CXCR1) and CXCR2. Here we characterize the unique mode of action of a small-molecule inhibitor (Repertaxin) of CXCR1 and CXCR2. Structural and biochemical data are consistent with a noncompetitive allosteric mode of interaction between CXCR1 and Repertaxin, which, by locking CXCR1 in an inactive conformation, prevents signaling. Repertaxin is an effective inhibitor of polymorphonuclear cell recruitment in vivo and protects organs against reperfusion injury. Targeting the Repertaxin interaction site of CXCR1 represents a general strategy to modulate the activity of chemoattractant receptors[2]. Non-cell-based assays for (Rac)-Reparixin include CXCR1/CXCR2 binding assays using radiolabeled IL-8 or receptor preparations. The compound's ability to inhibit IL-8 binding is measured, and IC₅₀ values are calculated. Receptor signaling assays can be used to assess inhibition of downstream signaling pathways. Standard analytical methods including HPLC, NMR, and mass spectrometry are used for compound characterization and purity assessment. |
| Cell Assay |
Migration.
Cell migration of human PMN and monocytes and rodent peritoneal PMN were evaluated in a 48-well microchemotaxis chamber with or without Repertaxin. Agonists (1 nM CXCL8, 10 nM N-formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLP), 10 nM CXCL1, 2.5 nM CCL2, 1 nM C5a, 5 nM rat and mouse CXCL1, and 2.5 nM rat and mouse CXCL2) were seeded in the lower compartment. The chemotaxis chamber was incubated for 45 min (human PMN), 1 h (rodent PMN), or 2 h (monocytes). L1.2 migration was evaluated by using 5-μm pore-size Transwell filters [2]. Cell-based assays for (Rac)-Reparixin use cells expressing CXCR1 and/or CXCR2 (e.g., neutrophils, transfected cell lines). Cells are treated with the compound and stimulated with IL-8. Chemotaxis is assessed using Boyden chamber or transwell assays. Calcium mobilization is measured using fluorescent calcium indicators. Cell proliferation, migration, and other functional assays are used to assess the compound's effects. Cytotoxicity is assessed using standard cell viability assays. |
| Animal Protocol |
C57BL/6J male mice treated with reparixin or vehicle were subjected to a middle cerebral artery occlusion procedure 1 h after the treatment. Ninety minutes after ischemia induction, the monofilament that prevented blood flow was removed. Twenty-four hours after the reperfusion procedure, behavioral changes, including motor signs, were analyzed with the SmithKline/Harwell/lmperial College/Royal Hospital/Phenotype Assessment (SHIRPA) battery. The animals were sacrificed, and brain tissue was removed for histological and biochemical analyses. Histological sections were stained with hematoxylin and eosin, neutrophil infiltration was estimated by myeloperoxidase activity and the inflammatory cytokine IL-iβ was measured by ELISA[1].
In vivo studies of (Rac)-Reparixin have been conducted in animal models. For anti-inflammatory studies, models of acute inflammation (e.g., carrageenan-induced paw edema, LPS-induced lung inflammation) are used. For ischemia-reperfusion injury, models of myocardial or cerebral ischemia are used. For cancer studies, tumor xenograft models are used. The compound is administered via various routes, and relevant endpoints are measured. |
| ADME/Pharmacokinetics |
(Rac)-Reparixin has a molecular formula of C₁₄H₂₁NO₃S and a molecular weight of approximately 283.39 g/mol. The CAS number is 957407-64-6. It is the racemic mixture of Reparixin, a non-competitive allosteric inhibitor of CXCR1 and CXCR2. The compound should be stored under recommended conditions. It is intended for research use only.
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| Toxicity/Toxicokinetics |
Specific toxicity data for (Rac)-Reparixin are limited. As a CXCR1/CXCR2 inhibitor, it may have effects on immune function. The compound has been studied in preclinical models with acceptable safety profiles. Standard laboratory safety practices should be followed when handling this compound, including the use of personal protective equipment. It is intended for research use only.
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| References |
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| Additional Infomation |
(Rac)-Reparixin is the racemic mixture of Reparixin, a non-competitive allosteric inhibitor of the chemokine receptors CXCR1 and CXCR2. Reparixin inhibits the binding of interleukin-8 (IL-8/CXCL8) to its receptors, blocking neutrophil chemotaxis and activation. The compound has been investigated for its potential in treating inflammatory conditions, ischemia-reperfusion injury, and cancer. CXCR1/CXCR2 signaling plays a critical role in inflammation, angiogenesis, and tumor progression. (Rac)-Reparixin is used as a research tool for studying CXCR1/CXCR2 signaling and its role in inflammation and cancer. It is for research use only.
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| Molecular Formula |
C14H21NO3S
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|---|---|
| Molecular Weight |
283.39
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| Exact Mass |
283.124
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| Elemental Analysis |
C, 59.34; H, 7.47; N, 4.94; O, 16.94; S, 11.31
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| CAS # |
957407-64-6
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| Related CAS # |
Reparixin;266359-83-5; 266359-93-7 (lysine salt)
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| PubChem CID |
6433115
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| Appearance |
White to off-white solid powder
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| Density |
1.1±0.1 g/cm3
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| Index of Refraction |
1.525
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| LogP |
2.66
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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 |
5
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| Heavy Atom Count |
19
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| Complexity |
389
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)CC1=CC=C(C=C1)C(C)C(=O)NS(=O)(=O)C
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| InChi Key |
KQDRVXQXKZXMHP-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C14H21NO3S/c1-10(2)9-12-5-7-13(8-6-12)11(3)14(16)15-19(4,17)18/h5-8,10-11H,9H2,1-4H3,(H,15,16)
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| Chemical Name |
2-[4-(2-methylpropyl)phenyl]-N-methylsulfonylpropanamide
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| Synonyms |
DF 1681Y; DF-1681Y; DF1681Y
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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 | 3.5287 mL | 17.6435 mL | 35.2871 mL | |
| 5 mM | 0.7057 mL | 3.5287 mL | 7.0574 mL | |
| 10 mM | 0.3529 mL | 1.7644 mL | 3.5287 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT05496868 | Recruiting | Drug: Reparixin 600mg Other: Matching Placebo |
Acute Respiratory Distress Syndrome, Adult |
Dompé Farmaceutici S.p.A | February 7, 2023 | Phase 2 |
| NCT05254990 | Recruiting | Drug: Reparixin Other: Placebo |
Infectious Pneumonia Severe COVID-19 |
Dompé Farmaceutici S.p.A | April 6, 2022 | Phase 3 |
| NCT05835466 | Recruiting | Drug: reparixin | Myelofibrosis (PMF) Post Essential Thrombocythemia Myelofibrosis (ET-MF) |
Icahn School of Medicine at Mount Sinai |
June 27, 2023 | Phase 2 |
| NCT04878055 | Completed | Drug: Reparixin Other: Placebo |
Pneumonia, Viral | Dompé Farmaceutici S.p.A | February 14, 2021 | Phase 3 |
| NCT02370238 | Completed | Drug: paclitaxel Drug: Reparixin |
Metastatic Breast Cancer | Dompé Farmaceutici S.p.A | July 29, 2015 | Phase 2 |
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