Ozanimod (RPC-1063) hydrochloride, a sphingosine 1-phosphate (S1P) receptor modulator that binds with high affinity selectively to S1P receptor subtypes 1 (S1P1) and 5 (S1P5). Ozanimod hydrochloride has modulate effect for hS1P 1 and hS1P 5 receptor with EC 50 s of 1.03 nM and 8.6 nM, respectively. Ozanimod hydrochloride can be used for the research of relapsing multiple sclerosis (MS).
Form:Solid
IC50& Target:S1PR1 1.03 nM (EC 50 ) S1PR5 8.6 nM (EC 50 )
In Vitro:Ozanimod (RPC-1063) hydrochloride has potency and intrinsic activity of S1P receptor modulators for S1P5 across species with [ 35 S]-GTPgS binding, and the EC 50 values of 1.03 nM, 1.29 nM, 0.90 nM, 1.02 nM and 0.61 nM for Human S1P 1 , Cynomolgus monkey S1P 1 , Mouse S1P 1 , Rat S1P1 and Canine S1P 1 , respectively; and the EC 50 values of 8.6 nM, 15.9 nM, 957.5 nM, 2032.7 nM and 1662.0 nM for Human S1P 5 , Cynomolgus monkey S1P 5 , Mouse S1P 5 , Rat S1P 5 and Canine S1P 5 , respectively. Ozanimod hydrochloride restores the potency with EC 50 from 958 nM for mS1P 5 to 6.7 nM for mS1P 5 _A120T to closely mirror the EC 50 for hS1P 5 of 8.6 nM by mutating the alanine in the mouse sequence. Ozanimod hydrochloride has binding affinity with K i values of 2.0 nM, 59.9 nM and 5.6 nM for hS1P 5 , mS1P 5 and mS1P 5 _A120T, respectively. Ozanimod hydrochloride has saturation binding of [ 3 H]-ozanimod to hS1P 5 , and mS1P 5 _A120T with K D values of 6.56 nM, 7.35 nM, respectively and also has saturation binding for [ 3 H]-A971432 to S1P 5 D value of 8.75 nM. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo:Ozanimod (RPC-1063) hydrochloride (oral gavage; 0.05, 0.2, or 1 mg/kg; once daily; for 14 consecutive days) exposures sufficient to engage S1P 1 , but not S1P 5 , 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 hydrochloride (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 hydrochloride (oral, 1 or 5 mg/kg, for 7 days) has good pharmacokinetics in mice [1] . MCE has not independently confirmed the accuracy of these methods. They are for reference only. 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: Animal Model\nC57BL/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**
