Etrasimod is a Selective and Orally Active S1P1 Receptor Antagonist

Etrasimod is a potent, selective, and orally available antagonist of the sphingosine-1-phosphate-1 (S1P1) receptor. And the IC50 value is 1.88 nM in CHO cells.

Firstly, in vitro, In CHO cells expressing HA-tagged S1P1. Etrasimod has an IC50 value of 1.88 nM. However, it exhibits a moderate agonism at human S1P4 and S1P5. But when it compared with S1P1, Etrasimod exhibits reduced potency and efficacy relative to S1P1.
Additionally, Etrasimod is devoid of any agonism or antagonism at human S1P2 and S1P3.

In vivo, this compound achieves good central exposure following oral dosing and possesses a favorable pharmacokinetic profile in multiple preclinical species.. The S1P1 activities maintain in different preclinical species. And, the IC50 values are 0.44 nM, 0.32 nM, and 0.34 nM for mice, rat, and dog respectively.
What’s more, Etrasimod has a relatively low systemic clearance (<4% of hepatic blood flow) and high Cmax across all species. In both dogs and monkey, a significant decrease in volume of distribution (Vss) is observed relative to rodents. The oral bioavailability is in the range of 40–100% in different species. And the terminal phase half-life varied from 6 h in monkeys, to as long as 29 h in dogs. Rat and monkey t1/2 values for siponimod (another S1P1 modulator currently in human trials) have been disclosed and are 6 and 19 h, respectively.

In a rat model, Etrasimod is similarly efficacious in a collagen-induced arthritis (CIA) model. Prophylactic oral administration in female Lewis rats results in a significant reduction in ankle diameters. And this result is similar to the rats with 1.0 mg/kg of fingolimod or 0.075 mg/kg of methotrexate. Etrasimod treatment suppresses CIA in rodents by inhibiting lymphocyte entry into arthritic joints.

In conclusion, Etrasimod is a potent S1P1 inhibitor, and can be used for cancer research.


[1]. Buzard DJ, et al.  ACS Med Chem Lett. 2014 Nov 4;5(12):1313-7.