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| Other Sizes |
| Targets |
(S)-SCH 563705 targets the chemokine receptors CXCR2 and CXCR1, which are part of the G protein-coupled receptor (GPCR) family. These receptors are primarily expressed on neutrophils and play critical roles in the inflammatory cascade by mediating neutrophil migration and activation in response to CXC chemokines such as Interleukin-8 (IL-8) and Gro-alpha (CXCL1). The compound acts as a dual antagonist, blocking both receptors simultaneously. It potently inhibits human CXCR2 and CXCR1 with IC50 values of 1.3 nM and 7.3 nM, respectively, and Ki values of 1 nM and 3 nM. Additionally, (S)-SCH 563705 effectively inhibits mouse CXCR2 with an IC50 of 5.2 nM, demonstrating cross-species activity.
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| ln Vitro |
In in vitro assays, (S)-SCH 563705 demonstrates potent and specific antagonistic activity against CXCR2 and CXCR1 receptors. Binding affinity studies show Ki values of 1 nM for CXCR2 and 3 nM for CXCR1, indicating high potency. Functional assays measuring chemotaxis inhibition demonstrate that the compound potently blocks both Gro-alpha and IL-8-induced human neutrophil migration (CXCR2 IC50 = 0.5 nM; CXCR1 IC50 = 37 nM). The compound shows no antagonist effect on Epac2 or protein kinase A activity, indicating selectivity for CXCR chemokine receptors. These in vitro data confirm that (S)-SCH 563705 effectively blocks neutrophil chemotaxis, which is the primary driver of CXCR-mediated inflammatory responses.
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| ln Vivo |
In vivo studies demonstrate that (S)-SCH 563705 exhibits favorable oral pharmacokinetic profiles and significant anti-inflammatory efficacy. In a mouse model of arthritis, oral administration of SCH 563705 dose-dependently decreases paw thickness and clearly reduces inflammation, as well as bone and cartilage degradation. Oral administration at 50 mg/kg in BALB/c female mice reduces blood Ly6G+ Ly6C+ neutrophil frequency while maintaining levels of Ly6GLy6Chi monocytes. Treatment at 3-30 mg/kg p.o. causes a dose-dependent elevation in plasma levels of the CXCR2 ligand CXCL1, consistent with receptor blockade. The compound also has good oral pharmacokinetic profiles in rats, mice, monkeys, and dogs, supporting its development for inflammatory diseases.
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| Enzyme Assay |
The in vitro receptor binding assay for (S)-SCH 563705 typically involves competitive radioligand binding using membranes expressing human CXCR1 or CXCR2 receptors. A generic protocol: membranes (5-20 microg protein) are incubated with 0.05-0.1 nM 125I-labeled IL-8 (or other radioligand) and varying concentrations of test compound (0.001 nM to 10 microM) in binding buffer (50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 0.5% BSA, pH 7.4) for 1-2 hours at room temperature. Bound radioactivity is separated by filtration through GF/B filters. Non-specific binding is determined using 100-fold excess unlabeled IL-8. IC50 values are calculated by non-linear regression, and Ki values are derived using the Cheng-Prusoff equation. For SCH 563705, this assay yielded Ki values of 1 nM for CXCR2 and 3 nM for CXCR1.
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| Cell Assay |
A standard in vitro cell-based assay for CXCR2/CXCR1 antagonists like (S)-SCH 563705 uses human peripheral blood neutrophils or neutrophil-like cell lines (e.g., HL-60 differentiated cells). A typical chemotaxis assay protocol: primary human neutrophils are isolated from whole blood using density gradient centrifugation. Cells are pre-treated with various concentrations of SCH 563705 (0.001 nM to 1 microM) for 15-30 minutes. Chemotaxis is then assessed in a 96-well Boyden chamber or transwell plate (3-5 microm pore size). The chemoattractant Gro-alpha (30 nM) or IL-8 (3 nM) is placed in the lower chamber, while pre-treated neutrophils are added to the upper chamber. After incubation at 37degC for 60-90 minutes, migrated cells in the lower chamber are quantified by measuring a metabolic activity marker (e.g., Calcein-AM fluorescence). Inhibition of chemotaxis is expressed as a percentage relative to vehicle control. For SCH 563705, this assay gave IC50 values of 0.5 nM for Gro-alpha-induced CXCR2-mediated migration and 37 nM for IL-8-induced CXCR1-mediated migration.
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| Animal Protocol |
The in vivo efficacy protocol for (S)-SCH 563705 in a mouse model of arthritis is as follows: Female BALB/c mice (6-8 weeks old) are immunized intradermally with 50 microL of 2 mg/mL chick type II collagen emulsified in Freund's Complete Adjuvant at the base of the tail. A booster immunization is given 21 days later. After arthritis onset (typically day 26-30), animals are randomized into groups based on clinical scores. SCH 563705 is administered orally at doses of 3, 10, or 30 mg/kg once or twice daily for 7-14 days (vehicle: 0.4% hydroxypropyl methyl cellulose). Disease progression is assessed daily using a clinical scoring system (0-4 per paw) measuring paw swelling and inflammation. Paw thickness is measured using calipers. At study termination (day 35-42), blood and paw tissues are collected for histopathological evaluation (inflammation, pannus formation, bone erosion, cartilage degradation) and for measuring plasma cytokine levels and compound concentrations. This protocol confirmed that SCH 563705 dose-dependently decreases paw thickness and reduces inflammation and joint degradation.
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| ADME/Pharmacokinetics |
(S)-SCH 563705 demonstrates favorable oral pharmacokinetic profiles across multiple species. In rats, mice, monkeys, and dogs, the compound exhibits good oral bioavailability and pharmacokinetic properties. Typical formulation for in vivo studies involves dissolving the compound in 0.4% hydroxypropyl methyl cellulose (HPMC) or a vehicle consisting of 5% DMSO, 30% PEG300, 5% Tween 80, and 60% saline. For oral administration, doses ranging from 3-50 mg/kg have been used in mouse studies. Following oral administration at 50 mg/kg in mice, the compound reduces blood Ly6G+ Ly6C+ neutrophil frequency, demonstrating target engagement. The compound's half-life and Cmax parameters are species-dependent, but generally support once- or twice-daily oral dosing for in vivo efficacy studies. Storage conditions for the powder are -20degC for up to 3 years, with solutions stable at -80degC for 6 months.
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| Toxicity/Toxicokinetics |
According to safety data sheet information, (S)-SCH 563705 is classified as a toxic substance containing a pharmaceutically active ingredient. Hazard statements indicate that the compound is harmful if swallowed and very toxic to aquatic life with long-lasting effects (H410). Under fire conditions, the compound may decompose and emit toxic fumes. Handling should only be performed by personnel trained and familiar with handling potent pharmaceutical ingredients. The compound is considered non-hazardous for transport under IATA regulations. The acute toxicity profile from animal studies is not publicly detailed, but the compound has been evaluated in multiple preclinical species (rats, mice, monkeys, dogs) for pharmacokinetic studies at doses up to 50 mg/kg, indicating a reasonable safety margin for experimental use. Standard safety precautions include chemical-resistant rubber gloves, safety goggles, and NIOSH/MSHA-approved respirator when handling.
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| References |
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| Additional Infomation |
SCH 563705 was discovered at Schering-Plough Research Institute and reported in a 2007 structure-activity relationship study optimizing furanyl cyclobutenediones for balanced dual-receptor potency and multi-species oral pharmacokinetics (Chao J, et al. Bioorg Med Chem Lett. 2007;17(13):3778-83). The S-enantiomer is the more active enantiomer, with the racemic mixture containing approximately 50% pharmacologically inactive enantiomer. Substitution with CXCR2-selective antagonists such as SCH 527123 (Navarixin) fails to recapitulate the dual CXCR1/CXCR2 blockade profile. The compound has been studied in various inflammatory conditions including arthritis, acute respiratory syndrome, and COPD. The molecular mechanism involves blocking neutrophil recruitment to sites of inflammation, thereby mitigating disease progression. No information about clinical trials or FDA approval for (S)-SCH 563705 is currently available; the compound remains at the preclinical research stage.
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| Molecular Formula |
C23H27N3O5
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| Molecular Weight |
425.48
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| Appearance |
White to off-white solid powder
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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 (~235.03 mM; with ultrasonication)
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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 | 2.3503 mL | 11.7514 mL | 23.5029 mL | |
| 5 mM | 0.4701 mL | 2.3503 mL | 4.7006 mL | |
| 10 mM | 0.2350 mL | 1.1751 mL | 2.3503 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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