Siponimod

Siponimod is an agonist of sphingosine-1-phosphate receptor 1 (S1P₁) and S1P5.^1,2 It is selective for S1P₁ and S1P₅ over S1P₂, S1P₃, and S1P₄ (EC₅₀s = 0.39, 0.98, >10,000, >1,000, and 750 nM, respectively, in GTP-γS binding assays).¹ Siponimod (10 nM) reduces demyelination induced by lysophosphatidylcholine or psychosine (Item Nos. 31594 | 20338) in mouse organotypic cerebellar slice cultures.³ It decreases plasma levels of urea and creatinine in a rat model of renal ischemia-reperfusion injury when administered at doses of 10 and 30 mg/kg.⁴ Siponimod (0.3 and 3 mg/kg) reduces disease severity in a rat model of experimental autoimmune encephalomyelitis (EAE).¹ Formulations containing siponimod have been used in the treatment of multiple sclerosis.

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1. Gergely, P., Nuesslein-Hildesheim, B., Guerini, D., et al. The selective sphingosine 1-phosphate receptor modulator BAF312 redirects lymphocyte distribution and has species-specific effects on heart rate. Br. J. Pharmacol. 167(5), 1035-1047 (2012).

2. Pan, S., Gray, N.S., Gai, W., et al. Discovery of BAF312 (siponimod), a potent and selective S1P receptor modulator. ACS Med. Chem. Lett. 4(3), 333-337 (2013).

3. O'Sullivan, C., Schubart, A., Mir, A.K., et al. The dual S1PR1/S1PR5 drug BAF312 (siponimod) attenuates demyelination in organotypic slice cultures. J. Neuroinflammation 13, 31 (2016).

4. Poirier, B., Briand, V., Kadereit, D., et al. A G protein-biased S1P₁ agonist, SAR247799, protects endothelial cells without affecting lymphocyte numbers. Sci. Signal. 13(634), eaax8050 (2020).