Dyckman Alaric J
Research and Development, Bristol-Myers Squibb Company , P.O. Box 4000, Princeton, New Jersey 08543-4000, United States.
J Med Chem. 2017 Jul 13;60(13):5267-5289. doi: 10.1021/acs.jmedchem.6b01575. Epub 2017 Mar 30.
The sphingoid base derived class of lipids (sphingolipids) is a family of interconverting molecules that play key roles in numerous structural and signaling processes. The biosynthetic pathway of the sphingolipids affords many opportunities for therapeutic intervention: targeting the ligands directly, targeting the various proteins involved in the interconversion of the ligands, or targeting the receptors that respond to the ligands. The focus of this article is on the most advanced of the sphingosine-related therapeutics, agonists of sphingosine-1-phosphate receptor 1 (S1P). The diverse structural classes of S1P agonists will be discussed and the status of compounds of clinical relevance will be detailed. An examination of how potential safety concerns are being navigated with compounds currently under clinical evaluation is followed by a discussion of the novel methods being explored to identify next-generation S1P agonists with improved safety profiles. Finally, therapeutic opportunities for sphingosine-related targets outside of S1P are touched upon.
鞘氨醇碱基衍生类脂质（鞘脂）是一类相互转化的分子家族，在众多结构和信号传导过程中发挥关键作用。鞘脂的生物合成途径为治疗干预提供了许多机会：直接靶向配体、靶向参与配体相互转化的各种蛋白质或靶向对配体作出反应的受体。本文重点关注最先进的与鞘氨醇相关的疗法，即鞘氨醇-1-磷酸受体1（S1P）的激动剂。将讨论S1P激动剂的不同结构类别，并详细介绍具有临床相关性的化合物的现状。在审视目前正在临床评估的化合物如何应对潜在安全问题之后，将讨论为识别具有更好安全性的下一代S1P激动剂而正在探索的新方法。最后，还会提及S1P之外与鞘氨醇相关靶点的治疗机会。
