Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors.
Imidazole-based sphingosine-1-phosphate transporter Spns2 inhibitors.
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DOI：
10.1016/j.bmcl.2023.129516
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发表时间：
2023-10
影响因子：
2.7
通讯作者：
Chris Shrader;D. Foster;Y. Kharel;Tao Huang;Kevin R. Lynch;W. Santos
中科院分区：
文献类型：
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作者：
Chris Shrader;D. Foster;Y. Kharel;Tao Huang;Kevin R. Lynch;W. Santos
鞘氨醇-1-磷酸（S1 P）是一种影响免疫细胞定位的趋化脂质。S1 P浓度梯度对于淋巴细胞从胸腺和次级淋巴组织适当流出是必要的。这种运输被S1 P受体调节剂阻断，预计S1 P转运蛋白（Spns 2）抑制剂通过重塑S1 P浓度梯度也会起到同样的作用。我们先前将SLF 1081851作为Spns 2抑制剂的原型，其提供了研究恶二唑核心和末端胺的重要性的支架。在本报告中，我们公开了一种结构-活性关系研究，通过将咪唑作为连接体和正电荷的替代物引入SLF 1081851中。在体外抑制HeLa细胞中Spns 2依赖的S1 P转运，鉴定了7作为一种抑制剂，IC 50为1.4 ± 0.3 µM。本文报告的SAR研究表明，咪唑鎓可以替代SLF 1081851中的末端胺，并且Spns 2抑制高度依赖于脂质烷基尾长。
Sphingosine-1-phosphate (S1P) is a chemotactic lipid that influences immune cell positioning. S1P concentration gradients are necessary for proper egress of lymphocytes from the thymus and secondary lymphoid tissues. This trafficking is interdicted by S1P receptor modulators, and it is expected that S1P transporter (Spns2) inhibitors, by reshaping S1P concentration gradients, will do the same. We previously reportedSLF1081851as a prototype Spns2 inhibitor, which provided a scaffold to investigate the importance of the oxadiazole core and the terminal amine. In this report, we disclose a structure–activity relationship study by incorporating imidazole as both a linker and surrogate for a positive charge inSLF1081851.In vitroinhibition of Spns2-dependent S1P transport in HeLa cells identified7bas an inhibitor with an IC50of 1.4 ± 0.3 µM. The SAR studies reported herein indicate that imidazolium can be a substitute for the terminal amine inSLF1081851and that Spns2 inhibition is highly dependent on the lipid alkyl tail length.