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Purity: ≥98%
CXCR2-IN-1 is a novel CNS (central nervous system) penetrant antagonist of CXCR2 with a pIC50 of 9.3. It was discovered by structure-activity relationship exploration of the historical biarylurea series. CXCR2-IN-1 demonstrated good developability potentials, a favorable PK profile, and nanomolar potency. More significantly, it demonstrated effectiveness in a model of cuprizone-induced demyelination when taken orally twice daily, supporting the idea that CXCR2 could be a useful target for therapy in the treatment of demyelinating illnesses like multiple sclerosis.
| Targets |
CXCR2 ( pIC50 = 9.3 )
C-X-C chemokine receptor type 2 (CXCR2) (Ki = 0.8 nM for human CXCR2; IC₅₀ = 1.2 nM for inhibiting CXCL8 (IL-8) binding to human CXCR2); >100-fold selectivity over CXCR1 (Ki = 120 nM), CXCR3 (Ki > 1000 nM), CXCR4 (Ki > 1000 nM), CCR1 (Ki > 1000 nM), CCR2 (Ki > 1000 nM), CCR5 (Ki > 1000 nM) [1] |
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| ln Vitro |
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| ln Vivo |
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| Enzyme Assay |
CXCR2 radioligand binding assay: Membranes from human CXCR2-expressing CHO cells were suspended in binding buffer (Tris-HCl, MgCl₂, BSA). CXCR2-IN-1 was serially diluted (0.001–1000 nM) and mixed with membranes and tritiated CXCL8. The mixture was incubated at 25°C for 60 minutes, then filtered through glass fiber filters to separate bound and free ligands. Radioactivity was measured by scintillation counting, and Ki/IC₅₀ values were calculated from displacement curves using nonlinear regression [1]
- CXCR2 selectivity binding assay: Membranes from cells expressing other chemokine receptors (CXCR1, CXCR3, etc.) were prepared as described for CXCR2. CXCR2-IN-1 was tested at concentrations up to 10 μM, and binding affinity (Ki) was determined to assess selectivity [1] |
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| Cell Assay |
CXCL8-induced calcium mobilization assay: Human CXCR2-expressing CHO cells were loaded with a calcium-sensitive fluorescent dye for 30 minutes at 37°C. CXCR2-IN-1 (0.001–100 nM) was preincubated with cells for 15 minutes, followed by stimulation with CXCL8 (10 nM). Fluorescence intensity was measured in real-time to assess calcium flux, and IC₅₀ values were derived from dose-response curves [1]
- Neutrophil chemotaxis assay: Human neutrophils were isolated from peripheral blood and resuspended in chemotaxis buffer. CXCR2-IN-1 (0.1–100 nM) was mixed with neutrophils, which were then added to the upper chamber of a transwell plate. CXCL8 (10 nM) was added to the lower chamber, and the plate was incubated at 37°C for 2 hours. Migrated neutrophils in the lower chamber were counted using a hemocytometer, and inhibition rates were calculated relative to vehicle control [1] |
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| Animal Protocol |
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| ADME/Pharmacokinetics |
In mice: After oral administration of CXCR2-IN-1 (10 mg/kg), the peak plasma concentration (Cₘₐₓ) was 0.9 μg/mL, the time to peak concentration (Tₘₐₓ) was 1 hour, the terminal half-life (t₁/₂) was 4.2 hours, and the oral bioavailability was 48% [1]
- Distribution in the central nervous system: As determined by LC-MS/MS, 2 hours after oral administration (10 mg/kg), the concentration of CXCR2-IN-1 in brain tissue reached 0.63 μg/g, and the brain-plasma ratio was 0.7 [1] - In vitro metabolic stability: In human liver microsomes, the metabolic half-life of CXCR2-IN-1 was 68 minutes; in mouse liver microsomes, the half-life was 75 minutes [1] |
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| Toxicity/Toxicokinetics |
Plasma protein binding rate: As determined by ultrafiltration, CXCR2-IN-1 had a plasma protein binding rate of 90% in human plasma and 88% in mouse plasma [1]
- Acute toxicity: In mice, no obvious toxic reactions (weight loss, convulsions or death) were observed within 7 days after oral administration of CXCR2-IN-1 at doses up to 100 mg/kg [1] |
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| References | ||
| Additional Infomation |
CXCR2-IN-1 is a potent, selective, and central nervous system-penetrating small molecule CXCR2 antagonist designed for the treatment of central nervous system (CNS) demyelinating diseases such as multiple sclerosis [1]. Its core mechanism of action is to block CXCR2-mediated recruitment of inflammatory cells (neutrophils, monocytes) to the CNS, thereby reducing neuroinflammation and demyelination [1]. CXCR2-IN-1's blood-brain barrier penetration is a key advantage for its targeted therapy of CNS inflammatory processes, as most CXCR2 antagonists lack effective brain access [1]. CXCR2-IN-1 exhibits significantly higher selectivity for CXCR2 than other chemokine receptors, thereby minimizing off-target effects on peripheral chemokine signaling [1].
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| Molecular Formula |
C₁₉H₂₀CL₂FN₃O₄S
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| Molecular Weight |
476.35
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| Exact Mass |
475.053
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| CAS # |
1873376-49-8
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| Related CAS # |
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| PubChem CID |
127020968
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| Appearance |
White to off-white solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
538.1±50.0 °C at 760 mmHg
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| Flash Point |
279.2±30.1 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.647
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| LogP |
4.64
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
30
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| Complexity |
702
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1C([H])=C([H])C(=C(C=1S(C1([H])C([H])([H])C([H])([H])N(C([H])([H])[H])C([H])([H])C1([H])[H])(=O)=O)O[H])N([H])C(N([H])C1C([H])=C([H])C([H])=C(C=1Cl)F)=O
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| InChi Key |
BJYOBCUGMDKPBM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H20Cl2FN3O4S/c1-25-9-7-11(8-10-25)30(28,29)18-12(20)5-6-15(17(18)26)24-19(27)23-14-4-2-3-13(22)16(14)21/h2-6,11,26H,7-10H2,1H3,(H2,23,24,27)
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| Chemical Name |
1-(2-chloro-3-fluorophenyl)-3-[4-chloro-2-hydroxy-3-(1-methylpiperidin-4-yl)sulfonylphenyl]urea
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| Synonyms |
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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 |
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| 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) |
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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 | 2.0993 mL | 10.4965 mL | 20.9930 mL | |
| 5 mM | 0.4199 mL | 2.0993 mL | 4.1986 mL | |
| 10 mM | 0.2099 mL | 1.0496 mL | 2.0993 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.
 ACS Med Chem Lett.2016 Feb 8;7(4):397-402. |
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 CNS penetrant CXCR2 antagonist22in a cuprizone model.ACS Med Chem Lett.2016 Feb 8;7(4):397-402. |
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