Ozanimod (RPC1063)|1306760-87-1|安捷凯

Background

Ozanimod (RPC1063) is a high orallybioavailable agonist of the sphingosine-1-phosphate receptor subtypes 1 (S1P1) and 5 (S1P5). S1P receptors belong to the family of G-protein-coupled receptor which contains five subtypes, denoting S1P1-5. S1P receptors are involved in coronary artery caliber,endothelial integrity, cardiac function, and lymphocyte recirculation [1].

In vitro: 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].

In vivo: 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].

Clinical trial: In the double-blind, placebo-controlled phase 2 trial in adult patients with moderate-to-severe ulcerative colitis, when treated with 1 mg ozanimod for 8 weeks, clinical response occurred in 57% of the patients while 0.5 mg ozanimod caused a 54% response. At week 32, the rate of clinical remission was 21% and 26% at the dose of 1 mg and 0.5 mg. The side effects were mainly anemia and headache [2].

参考文献:
[1].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.
[2].Sandborn WJ, Feagan BG1, et al.? Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis. N Engl J Med. 2016, 374(18):1754-1762.

Protocol

Cell experiment:

Representative histograms of transfected HEK293T cells expressing S1P1 receptors incubated with vehicle control or 1 μM RPC1063. HEK293T cells are incubated with increasing doses of Ozanimod (0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1 μM and 10 μM) for 1 h, or for 1 h followed by extensive washing to remove compound, then a 24 h recovery period and cell surface receptor expression is monitored[1].

Animal experiment:

Mice[1]Female C57BL/6 mice (60 total, 10 weeks of age) are immunized with Myelin Oligodendrocyte Glycoproteins (MOG) 35-55 peptide with complete Freund's adjuvant on day 0, and pertussis toxin is administered 2 h and 24 h later. At the first instance of clinical symptoms of EAE (limp tail), mice are randomized into treatment groups (n=10 per group) and administered the test compound, p.o., once daily for 14 days. Mice that develop disease earlier than 9 days post-immunization are not enrolled, as these often develop fulminant disease that does not respond to therapy. Test compounds are 0.2 and 0.6 mg/kg Ozanimod, 3 mg/kg FTY720 or vehicle (5% DMSO, 5% Tween-20, 90% 0.1 N HCl). Animals are monitored daily for body weight and clinical symptoms and scored. At the end of the study, mice are anaesthetized via inhalation of isoflurane bubbled with oxygen at 10-20 kPa, blood drawn via cardiac puncture to exsanguination and analysed by a veterinary haemoanalyser.

参考文献:

[1]. Scott FL, et al. Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity. Br J Pharmacol. 2016 Jun;173(11):1778-92.

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Ozanimod (RPC1063)

Ozanimod (RPC1063)详情

Background

Protocol

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