Etrasimod is a potent, selective and orally available antagonist of the sphingosine-1-phosphate-1 (S1P1) receptor with an IC50 value of 1.88 nM in CHO cells.
APD334 is a newly designed, highly specific antagonist targeting S1P1 receptors. In CHO cells expressing HA-tagged S1P1 receptors, APD334 demonstrates an IC50 value of 1.88 nM. While showing some degree of activation at human S1P4 and S1P5 receptors, this activation is notably weaker compared to S1P1, both in terms of potency and efficacy. Notably, APD334 does not exhibit any agonistic or antagonistic effects on human S1P2 and S1P3 receptors. Pharmacokinetic studies across various preclinical species demonstrate favorable central exposure and a promising pharmacokinetic profile. S1P1 receptor activity is maintained in mice (EC50=0.44 nM), rats (EC50=0.32 nM), dogs (EC50=0.34 nM), and monkeys (EC50=0.32 nM) [1].
Etrasimod 动物研究
Animal study
APD334 exhibits a relatively low systemic clearance (<4% of hepatic blood flow) and high Cmax across all species. Notably, both dogs and monkeys display a significant decrease in volume of distribution (Vss) compared to rodents. Oral bioavailability ranges from 40% to 100%, with terminal phase half-life ranging from 6 hours in monkeys to as long as 29 hours in dogs. The t1/2 values for siponimod (another S1P1 modulator currently in human trials) in rats and monkeys are disclosed as 6 and 19 hours, respectively [1].
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