Ponesimod

EC50: 5.7 nM

Ponesimod is a sphingosine-1-phosphate receptor 1 (S1P1) modulator.

Lymphocyte exit from lymph nodes and its recirculation into blood is reported to be controlled by S1P. The cellular receptor mediating lymphocyte exit is one of five S1P receptors, S1P1. Thus, the nonselective agonists for S1P1 lead to blood lymphocyte count reduction.

In vitro: Previous study found that ponesimod could activate S1P1-mediated signal transduction with high potency. Moreover, relative to the potency for S1P, the potency of ponesimod at human recombinant receptors was 4.4-fold higher for S1P1 and 150-fold lower for human S1P3. Thus, ponesimod was 650-fold more selective for human S1P1 over S1P3 than the endogeneous ligand [1].

In vivo: Animal study showed that the oral administration of ponesimod to rats resulted in a dose-dependent decrease of blood lymphocyte count, and the blood lymphocyte count returned to baseline within 48 h after discontinuation of ponesimod treatment. In addition, ponesimod prevented inflammatory cell accumulation, edema formation, as well as cytokine release in the skin of mice with delayed-type hypersensitivity. Furthermore, in rats with adjuvant-induced arthritis, ponesimod could also prevent the increase in paw volume and joint inflammation [2].

Clinical trial: Clinical data have shown a dose-dependent therapeutic effect of ponesimod, acceptable safety and tolerability. Furthermore, phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis [2].

References:
[1] Piali L, Froidevaux S, Hess P, Nayler O, Bolli MH, Schlosser E, Kohl C, Steiner B, Clozel M.  The selective sphingosine 1-phosphate receptor 1 agonist ponesimod protects against lymphocyte-mediated tissue inflammation. J Pharmacol Exp Ther. 2011 May;337(2):547-56.
[2] D'Ambrosio D, Freedman MS, Prinz J.  Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases. Ther Adv Chronic Dis. 2016 Jan;7(1):18-33.