RP101988 is the major active metabolite of Ozanimod and is a highly selective, potent agonist of the S1PR1 (sphingosine-1-phosphate receptor 1), with EC50s of 0.19nM and 32.8nM for S1PR1 and S1PR5, respectivlely[1]. Its selectivity for S1PR1 is significantly higher than that for other S1P receptor subtypes. S1PR1 plays a key regulatory role in the immune system, vascular endothelium, and nervous system. RP101988 can activate S1PR1, causing lymphocytes (T/B cells) to remain in lymphoid organs (such as lymph nodes and thymus), reducing their entry into the bloodstream and inflammatory sites[2].
In vitro, RP101988 (1μM) and other active metabolites of Ozanimod treated S1PR1-GFP overexpressing HEK-293 cells for 24 hours, showing similar pharmacological characteristics to their parent compounds[3]. Ozanimod is a weak substrate of P-glycoprotein (P-gp), while RP101988 is a substrate of P-gp and breast cancer resistance protein (BCRP) drug transporters[4].
References:
[1] Tran JQ, et al. Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study. Clin Pharmacol Drug Dev. 2018;7(3):263-276.
[2] Pérez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis. Drugs. 2021 Jun;81(9):985-1002.
[3] Selkirk JV, Yan YG, Ching N, Paget K, Hargreaves R. In vitro assessment of the binding and functional responses of ozanimod and its plasma metabolites across human sphingosine 1-phosphate receptors. Eur J Pharmacol. 2023;941:175442.
[4] Bencardino S, D'Amico F, Faggiani I, Bernardi F, Allocca M, Furfaro F, Parigi TL, Zilli A, Fiorino G, Peyrin-Biroulet L, Danese S. Efficacy and Safety of S1P1 Receptor Modulator Drugs for Patients with Moderate-to-Severe Ulcerative Colitis. J Clin Med. 2023 Jul 30;12(15):5014.
RP101988是Ozanimod的主要活性代谢产物，是一种高选择性、强效的 S1PR1（1-磷酸鞘氨醇受体1）激动剂，其对 S1PR1 和 S1PR5的EC50分别为0.19nM和 32.8nM[1]。它对 S1PR1 的选择性明显高于其他 S1P 受体亚型。S1PR1主要在免疫系统、血管内皮、神经系统中发挥关键调控作用。RP101988可以通过激活 S1PR1 ，促使淋巴细胞（T/B 细胞）滞留于淋巴器官（如淋巴结、胸腺），减少其进入血液循环和炎症部位[2]。
在体外，RP101988（1μM）以及其他Ozanimod的活性代谢物处理S1PR1-GFP过表达的HEK-293细胞24h，显示出与其母体化合物相似的药理学特征[3]。Ozanimod是P-糖蛋白（P-gp）的弱底物，而 RP101988 是P-gp和乳腺癌耐药蛋白（BCRP）药物转运蛋白的底物[4]。