Chun Jerold, Hartung Hans-Peter
Department of Molecular Biology, Helen L. Dorris Child and Adolescent Neuropsychiatric Disorder Institute, The Scripps Research Institute, La Jolla, CA, USA.
Clin Neuropharmacol. 2010 Mar-Apr;33(2):91-101. doi: 10.1097/WNF.0b013e3181cbf825.
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 5 S1P receptor subtypes, known as S1P subtypes 1-5 (S1P1-5), 4 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, whereas therapeutic administration significantly reduces clinical severity of EAE. Therapeutic efficacy observed in animal studies has been substantiated in phase 2 and 3 trials involving patients with relapsing or relapsing-remitting MS.
芬戈莫德（FTY720）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）的晚期临床试验中显示出疗效。在体内，芬戈莫德被磷酸化形成磷酸芬戈莫德，其类似于天然存在的1-磷酸鞘氨醇（S1P），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5种S1P受体亚型，称为S1P亚型1-5（S1P1-5），其中4种与磷酸芬戈莫德结合。这些受体在与MS相关的许多生物过程中涉及的多种细胞上表达。S1P1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。磷酸芬戈莫德最初通过高亲和力受体结合激活淋巴细胞S1P1，但随后诱导S1P1下调，阻止淋巴细胞从淋巴组织逸出，从而减少自身攻击性淋巴细胞浸润到中枢神经系统（CNS）。许多CNS细胞类型也表达S1P受体，并且已显示其影响细胞增殖、形态和迁移。芬戈莫德可穿过血脑屏障，因此可能具有直接的CNS效应，这使其有别于免疫靶向性MS疗法。对患有实验性自身免疫性脑脊髓炎（EAE，一种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，而治疗性给予则可显著降低EAE的临床严重程度。在动物研究中观察到的治疗效果已在涉及复发型或复发缓解型MS患者的2期和3期试验中得到证实。
