Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis.
Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis.
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口服芬戈莫德（FTY720）在多发性硬化症中的作用机制。
DOI：
10.1097/wnf.0b013e3181cbf825
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发表时间：
2010-03
影响因子：
1
通讯作者：
Hartung, Hans-Peter
中科院分区：
文献类型：
--
作者：
Chun, Jerold;Hartung, Hans-Peter
芬戈莫德（FTY 720）是一种一流的口服生物可利用化合物，已在治疗多发性硬化症（MS）的高级临床试验中显示出疗效。在体内，芬戈莫德被磷酸化形成芬戈莫德磷酸盐，其类似于天然存在的1-磷酸鞘氨醇（S1 P），一种细胞外脂质介质，其主要作用由同源G蛋白偶联受体介导。至少有五种S1 P受体亚型，称为S1 P1 -5，其中四种结合芬戈莫德磷酸盐。这些受体在广泛的细胞上表达，这些细胞参与与MS相关的许多生物学过程。S1 P1在免疫系统中起关键作用，调节淋巴细胞从淋巴组织进入循环。芬戈莫德磷酸盐最初通过高亲和力受体结合激活淋巴细胞S1 P1，但随后诱导S1 P1下调，阻止淋巴细胞从淋巴组织中流出，从而减少自身侵袭性淋巴细胞浸润到中枢神经系统（CNS）中。S1 P受体也由许多CNS细胞类型表达，并已显示影响细胞增殖、形态和迁移。芬戈莫德可以穿过血脑屏障，因此可能具有直接的CNS作用，与免疫靶向MS疗法不同。对患有实验性自身免疫性脑炎（EAE）（MS模型）的动物预防性给予芬戈莫德可完全预防EAE特征的发展，而治疗性给药可显著降低EAE的临床严重程度。在动物研究中观察到的疗效已在涉及复发或复发缓解型MS患者的II期和III期试验中得到证实。
Fingolimod (FTY720) is a first-in-class orally bioavailable compound that has shown efficacy in advanced clinical trials for the treatment of multiple sclerosis (MS). In vivo, fingolimod is phosphorylated to form fingolimod-phosphate, which resembles naturally occurring sphingosine 1-phosphate (S1P), an extracellular lipid mediator whose major effects are mediated by cognate G protein-coupled receptors. There are at least five S1P receptor subtypes, known as S1P1–5, four of which bind fingolimod-phosphate. These receptors are expressed on a wide range of cells that are involved in many biological processes relevant to MS. S1P1 plays a key role in the immune system, regulating lymphocyte egress from lymphoid tissues into the circulation. Fingolimod-phosphate initially activates lymphocyte S1P1 via high-affinity receptor binding, yet subsequently induces S1P1 down-regulation that prevents lymphocyte egress from lymphoid tissues, thereby reducing autoaggressive lymphocyte infiltration into the central nervous system (CNS). S1P receptors are also expressed by many CNS cell types and have been shown to influence cell proliferation, morphology and migration. Fingolimod crosses the blood–brain barrier and may therefore have direct CNS effects, distinguishing it from immunologically targeted MS therapies. Prophylactic administration of fingolimod to animals with experimental autoimmune encephalitis (EAE), a model of MS, completely prevents development of EAE features, while therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and phase 3 trials involving patients with relapsing or relapsing-remitting MS.