Siponimod

Siponimod (BAF-312) is an orally active, blood-brain barrier penetrant dual agonist of S1P1/S1P5, with EC₅₀ values of 0.39 nM and 0.98 nM, respectively. Siponimod induces S1P1 internalization, activates GIRK channels, inhibits lymphocyte egress, reduces peripheral lymphocyte counts, triggers transient bradycardia, prevents synaptic neurodegeneration, promotes remyelination, alleviates demyelination, and prevents the loss of GABAergic interneurons. Siponimod can be used in research related to multiple sclerosis^[1][2][3][4]. In Vitro:Siponimod (10-1000 nM; 4-13 h) induces significant and persistent internalization of human S1P₁ receptors in CHO cells. Obvious internalization is detectable even at concentrations as low as 10 nM, and the receptors remain localized intracellularly after drug washout^[1].
Siponimod regulates microglial function by reducing IL6 secretion in cultured microglia^[4].
Siponimod improves oligodendrocyte degeneration by alleviating demyelination in organotypic brain slice cultures^[4]. In Vivo:Siponimod (0.03-3 mg/kg; p.o.; daily; day 11 to day 34 post-immunization) dose-dependently suppresses established chronic experimental autoimmune encephalomyelitis in female DA rats, with significant efficacy observed at doses of 0.3 mg/kg and 3 mg/kg^[1].
Siponimod (0.14-1 mg/kg; p.o.; single dose) causes a rapid, dose-dependent reduction in peripheral lymphocyte counts in Lewis rats, with an ED₅₀ of 0.14 mg/kg at 6 hours post-dose, and counts return to normal within 48 hours^[2].