1306760-87-1

Ozanimod is a sphingosine-1-phosphate receptor 1 (S1P₁) and S1P₅ agonist. It induces GTPγS binding in cell membranes expressing human S1P₁ or S1P₅ (EC₅₀s = 0.41 and 11 nM, respectively) but not cell membranes expressing S1P₂ or S1P₃ receptors (EC₅₀s = >10,000 nM for both). Ozanimod (0.2 mg/kg) reduces the number of peripheral lymphocytes in rats. It reduces disease severity and the number of circulating lymphocytes in a mouse model of experimental autoimmune encephalomyelitis (EAE). Ozanimod (0.3 and 1 mg/kg) reduces disease severity and body weight loss in a mouse model of TNBS-induced colitis. Formulations containing ozanimod have been used in the treatment of relapsing multiple sclerosis and ulcerative colitis.

ozanimod(rpc1063) was a specific agonist for s1p1 and s1p5 receptors. the ec50values were 160 ± 60 pm and 410 ± 160 pm for s1p1 receptors in the inhibition of camp generation and[35s]-gtpγs binding. the 83% emax value of ozanimod against s1p5 receptor was 11 ± 4.3 nm. rpc1063 dose-dependently decreased s1p1 receptor re-expression on the cell surface and resulted in near complete and sustained loss of cell surface receptor expression at concentrations above 10 nm in s1p1 receptor-hek293t cells after 1 h incubation [1].

This orally available S1PR1 modulator (FW = 404.46 g/mol; CAS 1306760- 87-1; Solubility: 81 mg/mL DMSO; < 1 mg/mL H2O), also named RPC1063 and 5-[3-[ (1S) -2,3-dihydro-1-[ (2-hydroxyethyl) amino]-1H-inden- 4-yl]-1,2,4-oxadiazol-5-yl]-2- (1-methylethoxy) benzonitrile, selectively targets sphingosine 1-Phosphate (S1P) receptors, which mediate multiple processes, including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Ozanimod is specific for S1P1R (IC50 = 0.4 nM) and S1P5R, inducing S1P1R internalization and reversibly reducing the number of circulating B and CCR7+ T lymphocytes in vivo. It shows high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral ozanimod reduced inflammation and disease parameters in three autoimmune disease models, commending its use in the treatment of relapsing multiple sclerosis (RMS) and inflam- matory bowel disease (IBD). Indeed, the safety and efficacy of this modulator ozanimod in relapsing multiple sclerosis is indicated on the basis of a randomized, placebo-controlled, Phase 2 trial. Other SIPR1-directed immunomodulators include laquinimod, ponesimod, and siponimod.

the t1/2 of ozanimod was 4.7 h and 5.1 h in mice and rats after p.o. administration, respectively. about 81–82% decrease in circulating t lymphocyte was observed after dosing administration for 6 h, with a maximal blood concentration of 45 nm and 159 nm in rats and mice respectively. oral gavage of ozanimod dose-dependently reduced the disease score of mice in both doses (0.2 or 0.6 mg/kg/day) [1].

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scott f l, clemons b, brooks j, et al. ozanimod (rpc1063) is a potent sphingosine‐1‐phosphate receptor‐1 (s1p1) and receptor‐5 (s1p5) agonist with autoimmune disease‐modifying activity[j]. british journal of pharmacology, 2016.sandborn wj, feagan bg1, et al. ozanimod induction and maintenance treatment for ulcerative colitis. n engl j med. 2016, 374(18):1754-1762.