Ponesimod

A potent, selective, orally active S1P1 receptor agonist with EC50 of 9.1 nM; shows weak activity on S1P3 (EC50=123 nM) ; activates S1P1-mediated signal transduction with high potency (EC50 of 5.7 nM) ; causes maximal reduction of circulating lymphocytes at a dose of 3 mg/kg.Multiple Sclerosis Phase 3 Clinical (In Vitro) :Ponesimod activates human S1P1-5 receptors with EC50s of 5.7, >10000, 105, 1108 and 59.1 nM respectively in GTPγS binding assay.Ponesimod activates S1P1 receptors with EC50s of 5.7, 1.9, and 1.4 nM for human, rat, and mouse S1P receptors respectively. (In Vivo) :Ponesimod (30 and 175 mg/kg; once daily p.o. for 8 d) prevents delayed-type hypersensitivity in mice.Ponesimod (30 mg/kg by gavage 3 h before and 6 h after adjuvant injection followed by 100 mg/kg/day by administration as food admix for 18 days) prevents adjuvant-induced arthritis in rats.Ponesimod (0.3-100 mg/kg; a single oral gavage) causes a dose-dependent reduction in lymphocyte count, with a plateau effect being reached at 3 mg/kg in rats.Ponesimod (100 mg/kg; once daily oral gavage for 7 d) results in a lymphocyte count reduction to 1900 lymphocytes/μL, and this effect is maintained over the entire 7 days studies. Lymphocyte count returned to baseline levels within 48 h after discontinuation of dosing.