Molecular Pharmacology of Sphingosine 1-Phosphate

描述（由申请人提供）：直到最近，脂质介质鞘氨醇1-磷酸（S1 P）被视为细胞存活、运动和促有丝分裂因子。因此，S1 P受体拮抗剂通常被认为可用作抗癌药物。具有讽刺意味的是，S1 P受体激动剂-通过破坏淋巴细胞运输来调节免疫系统-的发现验证了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深刻地改变了81 P的格局。FTY 720正在进行肾移植和多发性硬化症的III期临床试验，正在招募老年痴呆症患者进行II期试验。尽管如此，关于芬戈莫德人，（调节免疫应答的鞘氨醇类似物，例如FTY 720）-芬戈莫德的构效关系（SAR）（前体形式和活性化合物），其活化对于在各种疾病模型中的功效是必需的S1 P受体类型，失活磷酸酶的性质，可能的非受体靶点的定义和消除已知毒性的必要性。因此，我们的实验计划可以简单地说，发现额外的新的化学实体，使受体选择性激动剂和拮抗剂（及其前药）的发展，评估是否S1 P1受体激动剂作为功能性拮抗剂，鉴定的失活磷酸酶和评估两个非受体的目标，酶S1 P裂解酶和autotaxin。我们计划的优势仍然是合成化学，遗传模型和分子药理学的结合。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，以及第一个S1 P受体拮抗剂。此外，我们发现2型鞘氨醇激酶是FTY 720和大多数其他芬戈莫德的活化酶。最低限度，我们的持续努力将显着延长SAR的化合物活性在S1 P受体，磷酸酶，鞘氨醇激酶和S1 P裂解酶。最理想的情况是，我们的工作将导致增加对一类新的口服药物的理解，这些药物用于治疗自身免疫性疾病，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一知识基础做出了贡献。此外，我们将使用这些工具化合物来确定此类治疗剂是否可用于治疗肾衰竭、血管损伤、动脉粥样硬化、癌症和其他病理。

DESCRIPTION (provided by applicant): 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 S1P signaling 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 and type 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.