Siponimod
[CAS# 1230487-00-9]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein) >> S1P receptor conditioner
• Name: Siponimod
• Synonyms: 1-(4-[1-[(E)-4-Cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl]-2-ethyl-benzyl)-azetidine-3-carboxylic acid; BAF 312
• Molecular Formula: C₂₉H₃₅F₃N₂O₃
• Molecular Weight: 516.60
• CAS Registry Number: 1230487-00-9
• SMILES: CCC1=C(C=CC(=C1)/C(=N/OCC2=CC(=C(C=C2)C3CCCCC3)C(F)(F)F)/C)CN4CC(C4)C(=O)O

Properties

• Solubility: Insoluble (1.7E^-4 g/L) (25 °C), Calc.^*, 10 mM (DMSO) (Expl.)
• Density: 1.24±0.1 g/cm³ (20 °C 760 Torr), Calc.^*
• Index of Refraction: 1.571, Calc.^*
• Boiling Point: 602.0±65.0 °C (760 mmHg), Calc.^*
• Flash Point: 317.9±34.3 °C, Calc.^*

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Risk Statements: H302-H315-H320-H335
• Safety Statements: P264-P270-P301+P312-P330

Discovery and Applications

Siponimod is a selective modulator of sphingosine-1-phosphate receptor subtypes 1 and 5. It was developed as a treatment for secondary progressive multiple sclerosis (SPMS) and has demonstrated efficacy in reducing the risk of disability progression. The compound was discovered through targeted medicinal chemistry efforts aimed at enhancing receptor selectivity and optimizing pharmacokinetic properties to enable central nervous system penetration.

The synthesis of siponimod involves a series of chiral transformations to ensure the desired enantiomeric purity, which is critical for its biological activity. The key step in the synthesis involves the construction of the core structure via asymmetric catalysis followed by functional group modifications to introduce the required side chains. This pathway was optimized to maximize yield and minimize impurities, resulting in a scalable process suitable for industrial production.

Siponimod's primary application lies in its use for managing SPMS, a progressive form of multiple sclerosis characterized by accumulating neurological deficits. By selectively modulating sphingosine-1-phosphate receptors, siponimod reduces lymphocyte egress from lymph nodes, thereby decreasing neuroinflammation. This mechanism helps preserve neurological function and delay the progression of disability in patients with SPMS.

References

2013. Discovery of BAF312 (Siponimod), a Potent and Selective S1P Receptor Modulator. ACS Medicinal Chemistry Letters.
DOI: 10.1021/ml300396r

2024. Multiple sclerosis: a narrative overview of current pharmacotherapies and emerging treatment prospects. Pharmacological reports : PR.
DOI: 10.1007/s43440-024-00642-0

2024. Anticancer Effects of BAF312 (Siponimod) in Epithelial Ovarian Cancer. Anticancer Research.
DOI: 10.21873/anticanres.17257