Siponimod

Siponimod (BAF312) is a potent, selective S1P1/S1P5 receptor modulator with EC50 of 0.39/0.0.98 nM, >1,000-fold selectivity over S1P2/3/4; suppresses ongoing disease symptoms in rat EAE, concentration-dependently increases GIRK current amplitude in atrial myocytes with EC50 of 15.8 nM, reduces peripheral absolute lymphocyte counts in vivo, exhibits potential as a treatment for immune-mediated diseases.Multiple Sclerosis Phase 3 Clinical(In Vitro):Siponimod (compound 32) exhibits selectivity to S1P1 and S1P5, and spares activity on the S1P2, S1P3 and S1P4 receptors.Siponimod (1 mM; 0-1 h) promotes internalization of S1P1 receptors, results 94% S1P1 receptors localized intracellularly at 1 h.Siponimod (0.001 nM-1 μM; 1 h) activates the GIRK channel in atrial myocytes, with an EC50 value of 15.8 nM in CHO cell line CCL-61.(In Vivo):Siponimod (1 g/kg; i.v.; single dose) shows low to moderate in monkey, but high in rat 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.Siponimod (0.3, 3 mg/kg; p.o.; once daily; 23 d) suppresses experimental autoimmune encephalomyelitis (EAE) in rats by internalizing S1P1 receptors.