Ozanimod (RPC1063)agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 CAS# 1306760-87-1 |
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| Cas No. | 1306760-87-1 | SDF | Download SDF |
| PubChem ID | 52938427 | Appearance | Powder |
| Formula | C23H24N4O3 | M.Wt | 404.46 |
| Type of Compound | N/A | Storage | Desiccate at -20°C |
| Synonyms | RPC-1063 | ||
| Solubility | DMSO : ≥ 29 mg/mL (71.70 mM) *"≥" means soluble, but saturation unknown. | ||
| Chemical Name | 5-[3-[(1S)-1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-propan-2-yloxybenzonitrile | ||
| SMILES | CC(C)OC1=C(C=C(C=C1)C2=NC(=NO2)C3=C4CCC(C4=CC=C3)NCCO)C#N | ||
| Standard InChIKey | XRVDGNKRPOAQTN-FQEVSTJZSA-N | ||
| Standard InChI | InChI=1S/C23H24N4O3/c1-14(2)29-21-9-6-15(12-16(21)13-24)23-26-22(27-30-23)19-5-3-4-18-17(19)7-8-20(18)25-10-11-28/h3-6,9,12,14,20,25,28H,7-8,10-11H2,1-2H3/t20-/m0/s1 | ||
| General tips | For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months. We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months. Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it. |
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| About Packaging | 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial. 2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial. 3. Try to avoid loss or contamination during the experiment. |
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| Shipping Condition | Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request. | ||
| Description | Ozanimod is a potent and selective S1P1 and S1P5 receptor agonist with EC50s of 410±160 pM and 11±4.3 nM in [35S]-GTPγS binding, respectively.In Vitro:Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1) and receptor-5 (S1P5) agonist. The EC50 values are subnanomolar for S1P1 receptors whether measuring inhibition of cAMP generation (160±60 pM) or [35S]-GTPγS binding (410±160 pM). The EC50 value for S1P5 receptor whether measuring inhibition [35S]-GTPγS binding (11±4.3 nM). Ozanimod demonstrates agonist activity at the S1P5 receptor [11±4.3 nM and 83% Emax (percentage of maximum stimulation)]. To determine whether Ozanimod induces sustained S1P1 receptor internalization, S1P1 receptor-HEK293T cells are incubated with different doses of Ozanimod in the presence of 10 μM cycloheximide to prevent translation of new S1P1 receptor protein. Cells are analysed after 1 h treatment, or, after the 1 h treatment washed thoroughly to remove Ozanimod and incubated with 1 μM Cycloheximide for a further 24 h. After a 1 h treatment Ozanimod induces significant loss of S1P1 receptor cell surface expression, similar in magnitude and potency to that seen with FTY720-P-treated cells. Following 1 h of treatment and a 24 h washout period, Ozanimod demonstrates a dose-dependent effect on S1P1 receptor re-expression on the cell surface, with near complete and sustained loss of cell surface receptor expression at concentrations above 10 nM[1].In Vivo:Ozanimod (RPC1063) is specific for S1P1 and S1P5 receptors, induces S1P1 receptor internalization and induces a reversible reduction in circulating B and CCR7+ T lymphocytes in vivo. Ozanimod shows high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral Ozanimod reduces inflammation and disease parameters in all three autoimmune disease models[1]. References: | |||||
Ozanimod (RPC1063) Dilution Calculator
Ozanimod (RPC1063) Molarity Calculator
| 1 mg | 5 mg | 10 mg | 20 mg | 25 mg | |
| 1 mM | 2.4724 mL | 12.3622 mL | 24.7243 mL | 49.4486 mL | 61.8108 mL |
| 5 mM | 0.4945 mL | 2.4724 mL | 4.9449 mL | 9.8897 mL | 12.3622 mL |
| 10 mM | 0.2472 mL | 1.2362 mL | 2.4724 mL | 4.9449 mL | 6.1811 mL |
| 50 mM | 0.0494 mL | 0.2472 mL | 0.4945 mL | 0.989 mL | 1.2362 mL |
| 100 mM | 0.0247 mL | 0.1236 mL | 0.2472 mL | 0.4945 mL | 0.6181 mL |
| * Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations. | |||||
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Ozanimod (RPC1063) is a high orally bioavailable 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 EC50 values 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].
References:
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.
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Ozanimod (RPC1063) is a potent sphingosine-1-phosphate receptor-1 (S1P1 ) and receptor-5 (S1P5 ) agonist with autoimmune disease-modifying activity.[Pubmed:26990079]
Br J Pharmacol. 2016 Jun;173(11):1778-92.
BACKGROUND AND PURPOSE: Sphingosine1-phosphate (S1P) receptors mediate multiple events including lymphocyte trafficking, cardiac function, and endothelial barrier integrity. Stimulation of S1P1 receptors sequesters lymphocyte subsets in peripheral lymphoid organs, preventing their trafficking to inflamed tissue sites, modulating immunity. Targeting S1P receptors for treating autoimmune disease has been established in clinical studies with the non-selective S1P modulator, FTY720 (fingolimod, Gilenya). The purpose of this study was to assess RPC1063 for its therapeutic utility in autoimmune diseases. EXPERIMENTAL APPROACH: The specificity and potency of RPC1063 (ozanimod) was evaluated for all five S1P receptors, and its effect on cell surface S1P1 receptor expression, was characterized in vitro. The oral pharmacokinetic (PK) parameters and pharmacodynamic effects were established in rodents, and its activity in three models of autoimmune disease (experimental autoimmune encephalitis, 2,4,6-trinitrobenzenesulfonic acid colitis and CD4(+) CD45RB(hi) T cell adoptive transfer colitis) was assessed. KEY RESULTS: RPC1063 was specific for S1P1 and S1P5 receptors, induced S1P1 receptor internalization and induced a reversible reduction in circulating B and CCR7(+) T lymphocytes in vivo. RPC1063 showed high oral bioavailability and volume of distribution, and a circulatory half-life that supports once daily dosing. Oral RPC1063 reduced inflammation and disease parameters in all three autoimmune disease models. CONCLUSIONS AND IMPLICATIONS: S1P receptor selectivity, favourable PK properties and efficacy in three distinct disease models supports the clinical development of RPC1063 for the treatment of relapsing multiple sclerosis and inflammatory bowel disease, differentiates RPC1063 from other S1P receptor agonists, and could result in improved safety outcomes in the clinic.
