Research Division, Mitsubishi Tanabe Pharma Corporation, 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
Pharmaceuticals (Basel). 2012 May 18;5(5):514-28. doi: 10.3390/ph5050514.
Sphingosine 1-phosphate (S1P), a lysophospholipid mediator, is generated from sphingosine by sphingosine kinases and binds five known cell surface receptors. S1P receptor 1 (S1P1) plays an essential role in lymphocyte egress from secondary lymphoid organs (SLO), as evinced by the inability of lymphocytes to exit from the SLO in mice lacking lymphocytic S1P1. Fingolimod hydrochloride (FTY720) is a first-in-class, orally active, S1P receptor modulator with a structure closely related to sphingosine. FTY720 was first synthesized by chemical modification of a natural product, myriocin. FTY720 is effectively converted to an active metabolite, FTY720 phosphate (FTY720-P) by sphingosine kinases. FTY720-P shows high affinity to 4 of the S1P receptors (S1P1, S1P3, S1P4, and S1P5). In particular, FTY720-P strongly induces internalization and degradation of S1P1, inhibits S1P responsiveness of lymphocytes in the SLO, and acts as a functional antagonist at lymphocytic S1P1. Consequently, FTY720 inhibits S1P1-dependent lymphocyte egress from the SLO to decrease circulation of lymphocytes including autoreactive Th17 cells and is highly effective in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Because FTY720 shows a superior efficacy in relapsing remitting MS patients compared to intramuscular interferon-β-1a (Avonex®), S1P1 is presumed to be a useful target for the therapy of MS.
鞘氨醇 1-磷酸（S1P）是一种溶血磷脂介质，由鞘氨醇激酶从鞘氨醇生成，并与五个已知的细胞表面受体结合。S1P 受体 1（S1P1）在淋巴细胞从次级淋巴器官（SLO）中迁出中发挥重要作用，这一点可以从缺乏淋巴细胞 S1P1 的小鼠中淋巴细胞无法从 SLO 中迁出得到证明。盐酸芬戈莫德（FTY720）是一种首创的、口服活性的 S1P 受体调节剂，其结构与鞘氨醇密切相关。FTY720 最初是通过对天然产物 myriocin 进行化学修饰而合成的。FTY720 被鞘氨醇激酶有效地转化为活性代谢物 FTY720 磷酸（FTY720-P）。FTY720-P 对 4 种 S1P 受体（S1P1、S1P3、S1P4 和 S1P5）具有高亲和力。特别是，FTY720-P 强烈诱导 S1P1 的内化和降解，抑制 SLO 中的淋巴细胞对 S1P 的反应性，并作为淋巴细胞 S1P1 的功能拮抗剂。因此，FTY720 抑制 S1P1 依赖性淋巴细胞从 SLO 迁出，减少包括自身反应性 Th17 细胞在内的淋巴细胞的循环，在实验性自身免疫性脑脊髓炎（EAE）中非常有效，EAE 是多发性硬化症（MS）的动物模型。由于 FTY720 在复发缓解型多发性硬化症患者中的疗效优于肌内注射干扰素-β-1a（Avonex®），因此 S1P1 被认为是 MS 治疗的有用靶点。
