Molecular Pharmacology of Sphingosine 1-Phosphate

直到最近，脂质介质鞘氨醇1-磷酸（S1 P）被视为细胞存活，运动和 促分裂因子因此，S1 P受体拮抗剂通常被认为可用作抗癌剂 毒品具有讽刺意味的是，这是发现，S1 P受体激动剂-作用于调节免疫系统 通过破坏淋巴细胞的运输-这验证了S1 P信号系统作为真正的药物靶点。 事实上，第一种研究药物FTY 720的巨大成功从根本上和 深刻地改变了81 P的格局FTY 720正在进行肾移植的III期临床试验， 多发性硬化症和老年痴呆症的第二阶段试验正在招募患者。 尽管如此，关于芬戈莫德（调节神经递质的鞘氨醇类似物）， 免疫应答，例如FTY 720）-芬戈莫德类药物（前体和 活性化合物），其活化对于在各种疾病中的功效是必需的S1 P受体类型 模型，失活磷酸酶的性质，可能的非受体靶点的定义和 需要消除已知的毒性。因此，我们的实验计划可以简单地说， 能够开发受体选择性激动剂和拮抗剂的其它新化学实体（和 它们的前药），评估S1 P1受体激动剂是否作为功能性拮抗剂，鉴定 失活磷酸酶和两个非受体靶点的评估，酶S1 P裂解酶和 自分泌运动因子我们计划的优势仍然是它的合成化学，遗传模型和 分子药理学 在过去的资助周期中，我们合成了选择性S1 P受体激动剂及其前体， 第一个S1 P受体拮抗剂。此外，我们发现鞘氨醇激酶2型是激活 FTY 720和大多数其他芬戈莫德的酶。至少，我们的持续努力将大大延长 对S1 P受体、磷酸酶、鞘氨醇激酶和S1 P裂解酶具有活性的化合物的SAR。最理想的情况是， 我们的工作将导致增加对一类新的自身免疫性疾病口服药物的了解 如多发性硬化症、炎症性肠病和I型糖尿病--事实上我们目前的化合物 已经为这个知识库做出了贡献。此外，我们将使用这些工具化合物来确定 这些治疗剂是否可用于治疗肾衰竭，血管损伤，动脉粥样硬化， 癌症和其他疾病。

Until recently, the lipid mediator sphingosine 1-phosphate (S1P) was viewed as a cell survival, motility and mitogenic factor. Therefore, S1P receptor antagonists were regularly imagined to be useful as anti-cancer drugs. Ironically, it was the discovery that S1P receptor agonists - acting to modulate the immune system by disrupting lymphocyte trafficking - that validated S1Psignaling systems as bone fide drug targets. Indeed, the spectacular success of the first-in-class investigational drug, FTY720, has fundamentally and profoundly altered the 81P landscape. FTY720 is in phase III clinical trials for kidney transplantation and multiple sclerosis and patients are being recruited for a phase II trial for senile dementia. Nevertheless, much remains to be learned about fingolimods (sphingosine analogs that modulate the immune response, e.g. FTY720) - the structure activity relationship (SAR) of fingolimods (pro-forms and active compounds), the S1P receptor types whose activation is necessary for efficacy in various disease models, the nature of the inactivating phosphatase(s), definition of possible non-receptor targets and the need to eliminate known toxicities. Thus our experimental plan can be stated succinctly as discovering additional new chemical entities to enable development of receptor selective agonists and antagonists (and their pro-drugs), assessment of whether S1P1 receptor agonists act as functional antagonists, identification of the inactivating phosphatases and assessment of two non-receptor targets, the enzymes S1P lyase and autotaxin. The strength of our program remains its combination of synthetic chemistry, genetic models and molecular pharmacology. In the past cycle of funding, we synthesized selective S1P receptor agonists and their pro-forms as well as the first S1P receptor antagonist. Further, we discovered that sphingosine kinase type 2 is the activating enzyme for FTY720 and most other fingolimods. Minimally, our continued efforts will extend dramatically the SAR of compounds active at S1P receptors, phosphotases, sphingosine kinases and S1P lyase. Optimally, our work will lead to the increased understanding of a new class of oral medications for autoimmune disease such as multiple sclerosis, inflammatory bowel diseases andtype I diabetes - indeed our current compounds have already contributed to this knowledge base. Further, we will use these tool compounds to determine whether such therapeutic agents could be useful in treating renal failure, vascular injury, atherosclerosis, cancer and other pathologies.