A benzo[b]thiophene-based selective type 4 S1P receptor agonist

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• 作者：Wooyoung Hur^a ; ¹ ; Hugh Rosen^b ; Nathanael S. Gray^a ; ^{Nathanael_Gray@dfci.harvard.edu}
• 关键词：Sphingosine-1-phosphate ; S1P receptor ; S1PR4 ; S1P4 ; Selective agonist
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：27
• 期：1
• 页码：1-5
• 全文大小：2622 K
• 卷排序：27

文摘

S1P receptors (S1PR1-5) are a group of GPCRs activated by a high affinity binding with S1P that have important roles in the regulation of the immune system. A potent S1PR agonist FTY720 is an immunomodulator used to treat multiple sclerosis and several ‘second generation’ drugs are under clinical development. Subtype-selective agonists have been reported for each S1PR isotype, some of which are used as pharmacological tools for functional studies. Here we report the discovery and initial characterization of compound 5c, a benzo[b]thiophene amino carboxylate which exhibits potent and selective agonist activity for S1PR4. Compound 5c has an EC50 = 200 nM as an agonist in GTPγ35S binding assay for S1PR4 and exhibits no activity against S1PR1,2,3,5. We confirmed its potent activity and decent S1PR subtype selectivity using biochemical and cellular assays.