Etrasimod

Etrasimod (APD334) 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. IC50 & Target:IC50: 1.88 nM (S1P1)^[1] In Vitro:APD334 is a structurally novel, selective, functional antagonist of S1P₁. In CHO cells expressing HA tagged S1P₁, APD334 is found to have an IC₅₀ value of 1.88 nM. Moderate agonism at human S1P₄ and S1P₅ is observed but is reduced relative to S1P₁, both in terms of potency and efficacy. APD334 is devoid of any agonism or antagonism at human S1P₂ and S1P₃. APD334 achieves good central exposure following oral dosing and possesses a favorable pharmacokinetic profile in multiple preclinical species. S1P₁ 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]. In Vivo:APD334 has a relatively low systemic clearance (<4% of hepatic blood flow) and high C_max across all species. In both dog and monkey a significant decrease in volume of distribution (Vss) is observed relative to rodent. Oral bioavailability is in the range of 40–100%, and the terminal phase half-life varied from 6 h in monkey, to as long as 29 h in dog. Rat and monkey t_1/2 values for siponimod (another S1P1 modulator currently in human trials) have been disclosed and are 6 and 19 h, respectively^[1].