Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors.
Structure-activity relationship studies and in vivo activity of guanidine-based sphingosine kinase inhibitors: discovery of SphK1- and SphK2-selective inhibitors.
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DOI：
10.1021/jm501760d
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发表时间：
2015-02-26
影响因子：
7.3
通讯作者：
Santos WL
中科院分区：
文献类型：
--
作者：
Patwardhan NN;Morris EA;Kharel Y;Raje MR;Gao M;Tomsig JL;Lynch KR;Santos WL
鞘氨醇1-磷酸（S1 P）是一种多效性信号分子，其充当五种G蛋白偶联受体（S1 P1 -5）的配体，所述受体的下游效应涉及多种重要病理学，包括镰状细胞病、癌症、炎症和纤维化。S1 P的合成由鞘氨醇激酶（SphK）亚型1和2催化，因此，该磷酸化步骤的抑制剂在理解SphK的生理功能中是关键的。迄今为止，SphK 1和2抑制剂的效力，选择性和体内稳定性，以确定这些激酶作为治疗靶点的潜力是缺乏的。在此，我们报告的设计，合成，和结构活性关系研究的胍基SphK抑制剂轴承恶二唑环的支架。我们的研究表明，SphK 2选择性抑制剂SLP 120701（Ki = 1 μM）可降低组织细胞淋巴瘤（U937）细胞中的S1 P水平。令人惊讶的是，与恶二唑和杂环之间的单个亚甲基单元的同源化在SLP 7111228中提供了SphK 1选择性抑制剂（Ki = 48 nM），这也降低了培养的U937细胞中的S1 P水平。然而，两种化合物的体内应用导致S1 P循环水平的对比效应。SLP 7111228给药降低了血液S1 P水平，而SLP 120701增加了S1 P水平。总之，这些化合物提供了一个体内化学工具包，以询问增加或减少S1 P水平的影响，以及这种操作是否会对疾病状态产生影响。
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P1–5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2, and hence, inhibitors of this phosphorylation step are pivotal in understanding the physiological functions of SphKs. To date, SphK1 and 2 inhibitors with the potency, selectivity, and in vivo stability necessary to determine the potential of these kinases as therapeutic targets are lacking. Herein, we report the design, synthesis, and structure–activity relationship studies of guanidine-based SphK inhibitors bearing an oxadiazole ring in the scaffold. Our studies demonstrate that SLP120701, a SphK2-selective inhibitor (Ki = 1 μM), decreases S1P levels in histiocytic lymphoma (U937) cells. Surprisingly, homologation with a single methylene unit between the oxadiazole and heterocyclic ring afforded a SphK1-selective inhibitor in SLP7111228 (Ki = 48 nM), which also decreased S1P levels in cultured U937 cells. In vivo application of both compounds, however, resulted in contrasting effect in circulating levels of S1P. Administration of SLP7111228 depressed blood S1P levels while SLP120701 increased levels of S1P. Taken together, these compounds provide an in vivo chemical toolkit to interrogate the effect of increasing or decreasing S1P levels and whether such a maneuver can have implications in disease states.