1. GPCR/G Protein
    Immunology/Inflammation
  2. CXCR

SCH 546738 

Cat. No.: HY-10017 Purity: 99.20%
Handling Instructions

SCH 546738 is a novel, potent and non-competitive CXCR3 antagonist, the affinity constant (Ki) of SCH 546738 binding to human CXCR3 receptor is determined to be 0.4 nM in multiple experiments.

For research use only. We do not sell to patients.

SCH 546738 Chemical Structure

SCH 546738 Chemical Structure

CAS No. : 906805-42-3

Size Price Stock Quantity
10 mM * 1 mL in DMSO USD 455 In-stock
Estimated Time of Arrival: December 31
1 mg USD 156 In-stock
Estimated Time of Arrival: December 31
5 mg USD 420 In-stock
Estimated Time of Arrival: December 31
10 mg USD 600 In-stock
Estimated Time of Arrival: December 31
50 mg USD 1800 In-stock
Estimated Time of Arrival: December 31
100 mg USD 2520 In-stock
Estimated Time of Arrival: December 31
200 mg   Get quote  
500 mg   Get quote  

* Please select Quantity before adding items.

    SCH 546738 purchased from MCE. Usage Cited in: Theranostics. 2017 Sep 26;7(17):4192-4203.

    Apoptosis related markers, ASK1, p-JNK, cleaved caspase 3 and cleaved PARP are measured by western blot in MCD-fed WT mice treated with vehicle or CXCR3 antagonists SCH546738 and AMG487.

    SCH 546738 purchased from MCE. Usage Cited in: J Hepatol. 2016 Jan;64(1):160-70.

    CXCR3 antagonists suppress MCD-induced steatohepatitis in vivo. CXCR3 protein levels are decreased after 10 days treatment of CXCR3 antagonists.

    SCH 546738 purchased from MCE. Usage Cited in: Nat Commun. 2017 Nov 17;8(1):1571.

    Activation of MAPK/ERK pathways after CXCR3 stimulation when cells are pretreated or not with CXCR3 antagonist SCH546738. Total ERK is used as loading control.

    SCH 546738 purchased from MCE. Usage Cited in: J Allergy Clin Immunol. 2016 Jul;138(1):114-122.e4.

    A selective CXCR3 receptor antagonist abrogates fibroblast migration to HRV MED (n=6).
    • Biological Activity

    • Protocol

    • Technical Information

    • Purity & Documentation

    • References

    Description

    SCH 546738 is a novel, potent and non-competitive CXCR3 antagonist, the affinity constant (Ki) of SCH 546738 binding to human CXCR3 receptor is determined to be 0.4 nM in multiple experiments.

    IC50 & Target[1]

    Human CXCR3

    0.4 nM (Ki)

    In Vitro

    The affinity of SCH 546738 binding to human CXCR3 receptor is determined by competition binding analysis using 35S radiolabeled SCH 535390 (a sulfonamide analog of the CXCR3 compound series with a Kd of 0.6 nM) as a competitive tracer. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. Competition of human CXCL10 and CXCL11 binding to human CXCR3 by SCH 546738 is determined at various concentrations of [125I]hCXCL10 and [125I]hCXCL11 around the Kd (50-100 pM) for the receptor. The IC50 of SCH 546738 is constant (~1 or 2 nM) and independent of the input concentrations of either [125I]hCXCL10 (25-500 pM) or [125I]hCXCL11 (12.5-250 pM), respectively[1].

    In Vivo

    SCH 546738 has strong cross-species activities with IC50 of 1.3 nM, 6.4 nM, 5.9 nM and 4.2 nM in inhibiting the binding of [125I]hCXCL10 to CXCR3 of monkey, dog, mouse and rat origin, respectively. SCH 546738 is a selective and potent CXCR3 antagonist with a good PK for in vivo studies. In addition, SCH 546738 has a favourable pharmacokinetic profile in rodents, the plasma concentrations of SCH 546738 in Lewis rat and C57BL/6 mouse over 24 hr post-dose. The AUC (0-24 hr) is 7.7 μM.hr in Lewis rat 10 mg/kg (mpk) and is 12.6 μM.hr in C57BL/6 mouse 30 mpk[1].

    Solvent & Solubility
    In Vitro: 

    DMSO : 4.5 mg/mL (9.14 mM; Need ultrasonic)

    Preparing
    Stock Solutions
    Concentration Solvent Mass 1 mg 5 mg 10 mg
    1 mM 2.0307 mL 10.1535 mL 20.3070 mL
    5 mM 0.4061 mL 2.0307 mL 4.0614 mL
    10 mM 0.2031 mL 1.0154 mL 2.0307 mL
    *Please refer to the solubility information to select the appropriate solvent.
    In Vivo:
    • 1.

      Add each solvent one by one:  corn oil

      Solubility: 1 mg/mL (2.03 mM); Suspended solution; Need ultrasonic and warming

    References
    Kinase Assay
    [1]

    A scintillation proximity assay is used for radioligand competition binding assays with some modifications. For each assay point, 1 µg of membrane is preincubated for 1 hr with 300 µg wheat germ agglutinin (WGA) coated SPA beads in the binding buffer (50 mM HEPES, 1 mM CaCl2, 5 mM MgCl2, 125 mM NaCl, 0.002% NaN3, 1.0% BSA) at room temperature. The beads are spun down, resuspended in the binding buffer and transferred to a 96-well Isoplate. The indicated concentrations of 125I-hCXCL10, 125I-hCXCL11 or 35S-SCH 535390 with a series of titrations of SCH 546738 (1-10 μM) are added to start the reaction. After indicated reaction times at room temperature, the amount of radioactivity bound to the SPA beads is determined with a Wallac 1450 Microbeta counter[1].

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Cell Assay
    [1]

    The preparation of human activated T cells is performed. Human peripheral blood lymphocytes are prepared by Ficoll-Hypaque centrifugation, depleted of monocytes, and stimulated for 2 days with 1 µg/mL PHA and 100 U/mL IL-2 in RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 2 mM L-Glutamine, 100 µg/mL Streptomycin, 100 U/mL Penecillin, 1% non-essential amino acids and 2 mM HEPES. Following stimulation, peripheral blood lymphocytes are cultured in above media containing 5% conditioned media for up to 15 days. uman activated T cell chemotaxis assays ae performed using 96-well ChemoTx microplates with a 3 µm filter. Activated T cells are washed with RPMI medium twice, and then resuspended in the medium containing 20% FBS. 1.25×105 cells/reaction are mixed with indicated concentrations of SCH 546738 (1, 10 or 100 nM) and placed on the filter. SCH 546738 and chemokines are mixed and placed in the bottom well of the ChemoTx system. After 2.5 hours incubation at 37°C/5% CO2, the cells are scraped off and the plate system is centrifuged for 5 minutes at 1000 RPM. The filter screen is then removed and the ChemoTx plate is inverted into a 96 well plate with a funnel plate. The plate system is centrifuged for 5 minutes at 1000 RPM. The volume in the wells is brought to 100 μL with assay buffer and the plates are rested for approximately 15 minutes at room temperature. The number of migrated cells is measured using the Cell Titer Glo Luminescent Assay. Chemotaxis is expressed as a chemotactic index, which is a ratio versus the one without chemokines[1]

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    Animal Administration
    [1]

    Mice[1]
    Female C57BL/6 mice are used. For immunization, 150 μg MOG35-55 peptide prepared by Princeton Biomolecules and 300 μg killed Mycobacterium tuberculosis are mixed in CFA and injected s.c. in two 50-μL injections over the flanks on day 1. Also, 200 ng of pertussis toxin is injected i.v. on days 0 and 2. SCH 546738 is administered orally 30 mpk in C57BL/6 mice twice daily. Dosing with SCH 546738 started at day 0, 24 h prior to MOG35-55 immunization (day 1). Mice are monitored daily and assessed for clinical signs of disease in a blinded fashion according to the following criteria: 0, no signs of disease; 1, tail paralysis; 2, limp tail and hind limb weakness; 3, hind limb paralysis; 4, hind limb plus forelimb paralysis; and 5, moribund or dead. Cumulative clinical scores are calculated by adding daily scores from the day of immunization until the end of the experiment. Mean clinical scores at separate days and mean maximal scores are calculated by adding the scores of individual mice and dividing with the number of mice in each group, including mice not developing signs of EAE.
    Rats[1]
    Male Lewis rats challenged by injection of 50 µL (30 mg) of a guinea pig spinal cord homogenate in complete Freund's adjuvant (CFA) into one footpad. SCH 546738 or 0.4% methylcellulose (vehicle) is orally administered at the indicated dose (0.2 mL) twice a day, starting on the day before transplantation until the day of graft rejection. SCH 546738 is administered orally at 10 mg/kg (mpk) in Lewis rats. To test whether SCH 546738 enhances the effect of conventional immunosuppressive reagent, the recipients are received treatment with subtherapeutic dose of CsA for one week combined with treatment with SCH 546738. Graft survival is analyzed using the log-rank test. The parametric data are analyzed by Student t test (2-tailed) using GraphPad InStat version.

    MCE has not independently confirmed the accuracy of these methods. They are for reference only.

    References
    Molecular Weight

    492.44

    Formula

    C₂₃H₃₁Cl₂N₇O

    CAS No.

    906805-42-3

    SMILES

    O=C(N)C1=NC(Cl)=C(N2CCN(C3CCN(CC4=CC=C(Cl)C=C4)CC3)[[email protected]@H](CC)C2)N=C1N

    Storage
    Powder -20°C 3 years
      4°C 2 years
    In solvent -80°C 6 months
      -20°C 1 month
    Shipping

    Room temperature in continental US; may vary elsewhere

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    Cat. No.: HY-10017