Siponimod (BAF312)

Alias:
Cat No.:V1505 Purity: ≥98%
Siponimod (BAF-312; WHO-9491; NVP-BAF-312; Mayzent) is anovel, potent and orally bioavailable S1P receptor modulator with immunomodulating activity.
Siponimod (BAF312) Chemical Structure CAS No.: 1230487-00-9
Product category: S1P Receptor
This product is for research use only, not for human use. We do not sell to patients.
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Other Forms of Siponimod (BAF312):

  • Siponimod fumarate (BAF312)
Official Supplier of:
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Purity & Quality Control Documentation

Purity: ≥98%

Product Description

Siponimod (BAF-312; WHO-9491; NVP-BAF-312; Mayzent) is a novel, potent and orally bioavailable S1P receptor modulator with immunomodulating activity. It can be used to treat medical conditions with significant immunopathology because of its high selectivity for S1P1 and S1P5 receptors (EC50 of 0.39 nM and 0.98 nM). It demonstrates selectivity over S1P2, S1P3, and S1P4 receptors that is >1000-fold. The metabolic clearance of BAF312 is high in rats, low to moderate in humans and monkeys, and low in dogs and mice, according to in vitro metabolism studies using liver microsomes.

Biological Activity I Assay Protocols (From Reference)
Targets
S1PR1 ( EC50 = 0.39 nM ); S1PR5 ( EC50 = 0.98 nM ); S1PR4 ( EC50 = 750 nM ); S1PR3 ( EC50 > 1000 nM ); S1PR2 ( EC50 > 10000 nM )
ln Vitro

In vitro activity: Siponimod (compound 32) shows selectivity for S1P1 and S1P5, while leaving the S1P2, S1P3, and S1P4 receptors unaffected[1].
Siponimod (1 mM; 0-1 h) stimulates S1P1 receptor internalization, with 94% of S1P1 receptors localized intracellularly at 1 h[2].
Siponimod (0.001 nM-1 μM; 1 h) has an EC50 value of 15.8 nM, which activates the GIRK channel in atrial myocytes in CHO cell line CCL-61[2].

ln Vivo
Siponimod (1 g/kg; i.v.; single dose) exhibits low to moderate levels in monkeys but high levels in rats in metabolism studies with liver microsomes. The absolute bioavailability is 50 and 71% in the rat and monkey, respectively, indicating no major presystemic first pass metabolism[1].
Siponimod (0.3, 3 mg/kg; p.o.; once daily; 23 d) internalizes S1P1 receptors to suppress experimental autoimmune encephalomyelitis (EAE) in rats[2].
Enzyme Assay
Centrifuging the cells at 26900 × g for 30 minutes at 4°C follows the homogenization of the cells. To re-suspend the membranes, mix 20 mM HEPES (pH 7.4), 100 mM NaCl, 10 mM MgCl2, 1 mM EDTA, and 0.1% fat-free BSA at a protein concentration of 2-3 mg/mL. The membranes used in the GTPγ[35S] binding assay are 75 mg protein/mL in 50 mM HEPES, 100 mM NaCl, 10 mM MgCl2, 20 μg/mL saponin and 0.1% fat-free BSA (pH 7.4), 5 mg/mL with a wheat-germ agglutinin-coated scintillation proximity assay-bead, and 10 μM GDP for 10–15 min. With the addition of 200 pM GTPγ[35S], the GTPγ[35S]-binding reaction is initiate. Once the plates have been at room temperature for 120 minutes, they are centrifuged at 300 × g for 10 minutes and then tallied.
Cell Assay
Analysis of CHO cells using flow cytometry reveals antagonist-mediated internalization of S1P1 receptors. An agonist is added to standard culture medium and Myc-tag hS1P1 cells are incubated for 1 hour at 37°C. The cells are then washed with PBS. While one aliquot is left in culture medium (without an agonist) at 37°C for three hours, the other is kept on ice for three hours (or twelve hours). First, the cells are incubated for 60 minutes at 4°C with either 4 μg/mL monoclonal mouse anti-C-myc IgG1 antibody or isotype control mouse IgG1. Next, they are incubated with 1 μg/mL of goat anti-mouse secondary conjugates that have been labeled with Alexa488, which is a fluorescent dye. Using 10,000 viable cells per sample, the cells are measured using flow cytometry.
Animal Protocol
Suspended in 1% aqueous carboxy-methylcellulose; 0.03, 0.3 and 3 mg/kg; oral givage
Encephalomyelitis (EAE) model rat
References

[1]. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br J Pharmacol. 2012 Nov;167(5):1035-47.

[2]. Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Med Chem Lett. 2013 Jan 4;4(3):333-7.

[3]. Prospects of siponimod in secondary progressive multiple sclerosis. Ther Adv Neurol Disord. 2018 Jul 17;11:1756286418788013.

[4]. Mechanism of Siponimod: Anti-Inflammatory and Neuroprotective Mode of Action. Cells. 2019 Jan 7;8(1):24.

These protocols are for reference only. InvivoChem does not independently validate these methods.
Physicochemical Properties
Molecular Formula
C29H35F3N2O3
Molecular Weight
516.6
Exact Mass
516.26
Elemental Analysis
C, 67.42; H, 6.83; F, 11.03; N, 5.42; O, 9.29
CAS #
1230487-00-9
Appearance
Solid powder
SMILES
CCC1=C(C=CC(=C1)/C(=N/OCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)/C)CN4CC(C4)C(=O)O
InChi Key
KIHYPELVXPAIDH-HNSNBQBZSA-N
InChi Code
InChI=1S/C29H35F3N2O3/c1-3-21-14-23(10-11-24(21)15-34-16-25(17-34)28(35)36)19(2)33-37-18-20-9-12-26(22-7-5-4-6-8-22)27(13-20)29(30,31)32/h9-14,22,25H,3-8,15-18H2,1-2H3,(H,35,36)/b33-19+
Chemical Name
1-[[4-[(E)-N-[[4-cyclohexyl-3-(trifluoromethyl)phenyl]methoxy]-C-methylcarbonimidoyl]-2-ethylphenyl]methyl]azetidine-3-carboxylic acid
Synonyms

BAF-312; WHO 9491; NVP-BAF-312; BAF 312; WHO-9491; NVP-BAF312; BAF312; NVP-BAF312-NX; WHO9491; NVP-BAF 312; NVP-BAF312-AEA; Siponimod; Mayzent

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: ~100 mg/mL (~193.6 mM)
Water: <1 mg/mL
Ethanol: ~44 mg/mL (~85.2 mM)
Preparing Stock Solutions 1 mg 5 mg 10 mg
1 mM 1.9357 mL 9.6787 mL 19.3573 mL
5 mM 0.3871 mL 1.9357 mL 3.8715 mL
10 mM 0.1936 mL 0.9679 mL 1.9357 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.

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Note: Chemical formula is case sensitive: C12H18N3O4  c12h18n3o4
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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.

(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.
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Clinical Trial Information
NCT Number Recruitment interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05376579 Active
Recruiting
Other: siponimod Active Secondary Progressive
Multiple Sclerosis
Novartis Pharmaceuticals June 17, 2022 N/A
NCT04933552 Recruiting Other: Siponimod Multiple Sclerosis Novartis Pharmaceuticals December 15, 2021 N/A
NCT04926818 Recruiting Drug: Siponimod
Drug: Ofatumumab
Multiple Sclerosis (MS) Novartis Pharmaceuticals October 5, 2021 Phase 3
NCT03623243 Completed Drug: Siponimod Multiple Sclerosis
Relapsing Multiple Sclerosis
Novartis Pharmaceuticals February 14, 2019 Phase 3
Biological Data
  • BAF312 (Siponimod)

    BAF312 suppresses ongoing disease symptoms in rat EAE. Br J Pharmacol. 2012 Nov;167(5):1035-47.
  • BAF312 (Siponimod)

    BAF312 activates human atrial myocytes via S1P1. Effects of BAF312 and for comparison S1P on GIRK current recorded from acutely isolated human atrial myocytes. Br J Pharmacol. 2012 Nov;167(5):1035-47.
  • BAF312 (Siponimod)

    Mean changes in ALC after multiple daily doses of BAF312 in healthy subjects. Br J Pharmacol. 2012 Nov;167(5):1035-47.
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