Ozanimod (RPC-1063) 是一种鞘氨醇 1-磷酸 (S1P) 受体调节剂，可高亲和力地选择性结合 S1P 受体亚型 1 (S1P1) 和 S1P5 (S1P5)。Ozanimod 对 hS1P1和 hS1P5受体具有调节作用，EC50值分别为 1.03 nM 和 8.6 nM。Ozanimod 可用于复发性多发性硬化 (MS) 的研究。
| 生物活性 | Ozanimod (RPC-1063), asphingosine 1-phosphate (S1P)receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P1) and 5 (S1P5). Ozanimod has modulate effect for hS1P1and hS1P5receptor withEC50s of 1.03 nM and 8.6 nM, respectively. Ozanimod can be used for the research of relapsing multiple sclerosis (MS)[1]. |
| IC50& Target | S1PR1 1.03 nM (EC50) | S1PR5 8.6 nM (EC50) |
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体外研究
(In Vitro) | Ozanimod (RPC-1063) has potency and intrinsic activity of S1P receptor modulators for S1P5 across species with [35S]-GTPgS binding, and the EC50values of 1.03 nM, 1.29 nM, 0.90 nM, 1.02 nM and 0.61 nM for Human S1P1, Cynomolgus monkey S1P1, Mouse S1P1, Rat S1P1 and Canine S1P1, respectively; and the EC50values of 8.6 nM, 15.9 nM, 957.5 nM, 2032.7 nM and 1662.0 nM for Human S1P5, Cynomolgus monkey S1P5, Mouse S1P5, Rat S1P5and Canine S1P5, respectively[1].
Ozanimod restores the potency with EC50from 958 nM for mS1P5to 6.7 nM for mS1P5_A120T to closely mirror the EC50for hS1P5of 8.6 nM by mutating the alanine in the mouse sequence[1].
Ozanimod has binding affinity with Kivalues of 2.0 nM, 59.9 nM and 5.6 nM for hS1P5, mS1P5and mS1P5_A120T, respectively[1].
Ozanimod has saturation binding of [3H]-ozanimod to hS1P5, and mS1P5_A120T with KDvalues of 6.56 nM, 7.35 nM, respectively and also has saturation binding for [3H]-A971432 to S1P5Dvalue of 8.75 nM[1].
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体内研究
(In Vivo) | Ozanimod (RPC-1063) (oral gavage; 0.05, 0.2, or 1 mg/kg; once daily; for 14 consecutive days) exposures sufficient to engage S1P1, but not S1P5, resulted in reduced circulating lymphocytes, disease scores, and body weight loss; reduced inflammation, demyelination, and apoptotic cell counts in the spinal cord; and reduced circulating levels of the neuronal degeneration marker, neurofilament light[1].
Ozanimod (oral gavage; 5 mg/kg; once-daily) prevented axonal degradation and myelin loss during toxin challenge but did not facilitate enhanced remyelination after intoxication[1].
Ozanimod (oral, 1 or 5 mg/kg, for 7 days) has good pharmacokinetics in mice[1].
| Animal Model: | Experimental Autoimmune Encephalomyelitis Model[1] | | Dosage: | 0.05, 0.2, or 1 mg/kg | | Administration: | oral gavage; 0.05, 0.2, or 1 mg/kg; once daily; for 14 consecutive days | | Result: | Attenuated body weight loss, terminal disease scores were significantly attenuated with the 0.2 and 1 mg/kg doses and ALCs were significantly reduced in all dose groups.
Reduced spinal cord inflammation and demyelination, as well as attenuated the number of spinal cord apoptotic cells, and significantly reduced the levels of circulating neurofilament light at the top dose of 1 mg/kg. |
| Animal Model: | Cuprizone/Rapamycin Demyelination Model[1] | | Dosage: | 5 mg/kg | | Administration: | oral gavage; 5 mg/kg; once-daily | | Result: | Protected neuronal axons, preventing breakage and ovoid formation in the corpus callosum of CPZ/Rapa treated mice.
Significantly attenuated the extent to which the corpus callosum demonstrated reduced myelin content as visualized by MRI.
Did not result in enhanced myelin content. |
| Animal Model: | C57BL/6J mice[1] | | Dosage: | 1 or 5 mg/kg | | Administration: | oral, 1 or 5 mg/kg, for 7 days | | Result: | | Dose | Terminal body weight % versus day 1 | Spinal cord inflammation Foci per 20 cells | Spinal cord demyelination Score 0–5 | Spinal cord apoptotic cells Count per section | Plasma NfL pg/ml | | Vehicle (5% DMSO, 5%Tween 20, 90% water) | 86.4 ± 3.2 | 8.50 ± 1.21 | 2.00 ± 0.15 | 2.25 ± 0.53 | 4.37 ± 0.89 | | Ozanimod (0.05 mg/kg) | 85.8 ± 2.7 | 5.00 ± 1.03* | 0.91 ± 0.21*** | 1.08 ± 0.23* | 3.53 ± 0.46 | | Ozanimod (0.2 mg/kg) | 95.7 ± 3.1* | 3.54 ± 0.49*** | 0.73 ± 0.14 *** | 0.91 ± 0.28* | 2.62 ± 0.46 | | Ozanimod (1 mg/kg) | 102.8 ± 1.8* | 2.67 ± 0.56*** | 0.33 ± 0.14 *** | 0.60 ± 0.19** | 1.91 ± 0.34** |
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| 运输条件 | Room temperature in continental US; may vary elsewhere. |
| 储存方式 | | Powder | -20°C | 3 years | | 4°C | 2 years | | In solvent | -80°C | 6 months | | -20°C | 1 month |
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| 溶解性数据 | In Vitro: DMSO : ≥ 29 mg/mL(71.70 mM) *"≥" means soluble, but saturation unknown. 配制储备液 | 1 mM | 2.4724 mL | 12.3622 mL | 24.7243 mL | | 5 mM | 0.4945 mL | 2.4724 mL | 4.9449 mL | | 10 mM | 0.2472 mL | 1.2362 mL | 2.4724 mL |
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