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[摘要]：Sphingosine 1-phosphate (SIP) is an example of a lysophospholipid, a class of bioactive lipids with extracellular effects mediated by G protein-coupled receptors. There are five known S1P receptor subtypes, S1P(1-5). S1P receptors have gained increasing relevance for the therapeutic treatment of multiple sclerosis (MS) through studies of a breakthrough compound, FTY720, (known clinically as fingolimod), which has the potential to become the first oral therapy for the first-line treatment of relapsing-remitting MS. FTY720 is a prodrug that, when phosphorylated in vivo, becomes a nonselective S1P receptor agonist at four of the five receptors, S1P(1,3,4,5), supporting receptor modulation at one or more of these SIP receptors in treating MS, although receptor subtypes and forms of modulation may be varied and diverse. Emerging understanding of the receptor mechanism of action in MS suggests possible strategies for going forward, although this is complicated by uncertainties over the complete mechanism of action that may interrupt not only inflammatory insults, but may also directly modulate central nervous system activities. Nevertheless, robust experimental and clinical experience with FTY720 portends the development of new compounds having improved efficacy and/or safety profiles, which could herald a new generation of oral MS therapies based on SIP receptor modulation. |
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