SCH-546738

Alias: SCH-546738; SCH 546738; SCH546738

Cat No.:V4668 Purity: ≥98%

COA Product Data Instructions for use SDS

SCH-546738 (SCH546738) is a novel, potent selective, and non-competitive CXCR3 antagonist with potential anticancer, immunomodulatory and antiinflammatory activities.

SCH-546738 Chemical Structure CAS No.: 906805-42-3
Product category: New7

This product is for research use only, not for human use. We do not sell to patients.

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Citations by Top Journals: Nature, Cell, Science, etc.

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Nature 2024 Dec 18.

Nature 2021, 597(7874):119-125.

Cell 2020,183:1202-1218.e25.

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Cell 2020,183:1202-1218.e25.

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Nature 2021,597(7874):119-125.

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Purity & Quality Control Documentation

Current batch：

Purity: ≥98%

COA

MSDS

Instructions

Product Description
Bioactivity & Protocols
Physicochemical Properties
Solubility Data
Calculators

Product Description

SCH-546738 (SCH546738) is a novel, potent selective, and non-competitive CXCR3 antagonist with potential anticancer, immunomodulatory and antiinflammatory activities. It inhibits CXCR3 with affinity constant (Ki) (binding to human CXCR3 receptor) of 0.4 nM in multiple experiments. It attenuates the development of autoimmune diseases and delays graft rejection.

Biological Activity I Assay Protocols (From Reference)

ln Vitro

SCH 546738's affinity for binding to the human CXCR3 receptor was assessed through a competitive binding assay, wherein the competitive tracer was 35S radiolabeled SCH 535390, a sulfonamide analog belonging to the CXCR3 compound series with a Kd of 0.6 nM. Furthermore, with an IC50 ranging from 0.8 to 2.2 nM, SCH 546738 non-competitively displaces radiolabeled CXCL10 and CXCL11 in human CXCR3. With an IC90 of roughly 10 nM, SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells [1].

ln Vivo

With IC50s of 1.3, 6.4, 5.9, and 4.2 nM, respectively, SCH 546738 exhibits substantial cross-species action against the binding of [125I]hCXCL10 to CXCR3 in monkeys, dogs, mice, and rats. According to in vivo research, SCH 546738 is a strong and selective CXCR3 antagonist with good PK [1].

Enzyme Assay

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 (SCH546738) (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].

Cell Assay

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]

Animal Protocol

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 Freunds 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.

References

[1]. A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection. BMC Immunol. 2012 Jan 10;13:2.

[2]. CXC chemokine receptor 3 promotes steatohepatitis in mice through mediating inflammatory cytokines, macrophages and autophagy. J Hepatol. 2016 Jan;64(1):160-70.

[3]. STAT3 in CD8+ T Cells Inhibits Their Tumor Accumulation by Downregulating CXCR3/CXCL10 Axis. Cancer Immunol Res. 2015 Aug;3(8):864-870.

These protocols are for reference only. InvivoChem does not independently validate these methods.

Physicochemical Properties

Molecular Formula	C23H31N7OCL2
Molecular Weight	492.44454
Exact Mass	491.197
CAS #	906805-42-3
PubChem CID	11995774
Appearance	White to light yellow solid powder
Density	1.327 g/cm3
Boiling Point	628.202ºC at 760 mmHg
Flash Point	333.725ºC
LogP	4.252
Hydrogen Bond Donor Count	2
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	6
Heavy Atom Count	33
Complexity	642
Defined Atom Stereocenter Count	1
SMILES	CC[C@H]1CN(CCN1C2CCN(CC2)CC3=CC=C(C=C3)Cl)C4=NC(=C(N=C4Cl)C(=O)N)N
InChi Key	UYDYJFWSPRQEAX-KRWDZBQOSA-N
InChi Code	InChI=1S/C23H31Cl2N7O/c1-2-17-14-31(23-20(25)28-19(22(27)33)21(26)29-23)11-12-32(17)18-7-9-30(10-8-18)13-15-3-5-16(24)6-4-15/h3-6,17-18H,2,7-14H2,1H3,(H2,26,29)(H2,27,33)/t17-/m0/s1
Chemical Name	3-Amino-6-chloro-5-[(3S)-4-[1-[(4-chlorophenyl)methyl]piperidin-4-yl]-3-ethylpiperazin-1-yl]pyrazine-2-carboxamide
Synonyms	SCH-546738; SCH 546738; SCH546738
HS Tariff Code	2934.99.9001
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)

Solubility Data

Solubility (In Vitro)	DMSO : ~4.5 mg/mL (~9.14 mM) H2O : ~1 mg/mL (~2.03 mM)
Solubility (In Vivo)	Solubility in Formulation 1: 1 mg/mL (2.03 mM) in Corn Oil (add these co-solvents sequentially from left to right, and one by one), suspension solution; with heating and sonication. (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		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

*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.

Calculator

Mass

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Molarity Calculator allows you to calculate the mass, volume, and/or concentration required for a solution, as detailed below:

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See Example

An example of molarity calculation using the molarity calculator is shown below:
What is the mass of compound required to make a 10 mM stock solution in 5 ml of DMSO given that the molecular weight of the compound is 350.26 g/mol?

Enter 350.26 in the Molecular Weight (MW) box
Enter 10 in the Concentration box and choose the correct unit (mM)
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The answer of 17.513 mg appears in the Mass box. In a similar way, you may calculate the volume and concentration.

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Dilution Calculator allows you to calculate how to dilute a stock solution of known concentrations. For example, you may Enter C1, C2 & V2 to calculate V1, as detailed below:

What volume of a given 10 mM stock solution is required to make 25 ml of a 25 μM solution?
Using the equation C1V1 = C2V2, where C1=10 mM, C2=25 μM, V2=25 ml and V1 is the unknown:

Enter 10 into the Concentration (Start) box and choose the correct unit (mM)
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Enter 25 into the Volume (End) box and choose the correct unit (mL)
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The answer of 62.5 μL (0.1 ml) appears in the Volume (Start) box

Molecular formula

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g/mol

Molecular Weight Calculator allows you to calculate the molar mass and elemental composition of a compound, as detailed below:

Note: Chemical formula is case sensitive: C12H18N3O4 c12h18n3o4
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Definitions of molecular mass, molecular weight, molar mass and molar weight:

Molecular mass (or molecular weight) is the mass of one molecule of a substance and is expressed in the unified atomic mass units (u). (1 u is equal to 1/12 the mass of one atom of carbon-12)
Molar mass (molar weight) is the mass of one mole of a substance and is expressed in g/mol.

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The answer appears in the Volume (to add to vial) box

In vivo Formulation Calculator (Clear solution)

Step 1: Enter information below (Recommended: An additional animal to make allowance for loss during the experiment)

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Step 2: Enter in vivo formulation (This is only a calculator, not the exact formulation for a specific product. Please contact us first if there is no in vivo formulation in the solubility section.)

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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.

Note： (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.