Synthesis of benzimidazole based analogues of sphingosine-1-phosphate:: discovery of potent, subtype-selective S1P4 receptor agonists
Synthesis of benzimidazole based analogues of sphingosine-1-phosphate:: discovery of potent, subtype-selective S1P4 receptor agonists
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DOI：
10.1016/j.bmcl.2004.07.030
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发表时间：
2004-10-04
影响因子：
2.7
通讯作者：
Macdonald, TL
中科院分区：
文献类型：
--
作者：
Clemens, JJ;Davis, MD;Macdonald, TL
鞘氨醇-1-磷酸（SIP）是一种具有生物活性的溶血磷脂，能够通过与g蛋白偶联受体的SlP家族相互作用诱导广泛的细胞反应。该受体家族的一员SlP(4)在淋巴系统中高度且几乎完全表达，并与细胞形状和运动的调节有关。本报告描述了几种有效的苯并咪唑类SlP(4)受体选择性激动剂的合成。例如，使用[γ - s -35]GTP结合试验，化合物9b在SlP(4)受体上的EC50 = 36 nM，而内源性配体的EC50 = 37 nM。我们还报道了改变C2位置的立体化学，C1和C2位置的甲基化以及类似物的醇和磷酸盐头基团之间的活性差异的影响。(C) 2004 Elsevier Ltd.版权所有。
Sphingosine-1-phosphate (SIP) is a biologically active lysophospholipid with the capacity to induce a broad range of cellular responses via its interaction with the SlP family of G-protein coupled receptors. A member of this receptor family, SlP(4), is highly and almost exclusively expressed in the lymphoid system and has been implicated in regulation of cell shape and motility. This report describes the synthesis of several potent benzimidazole based SlP(4) receptor selective agonists. For instance, compound 9b displayed an EC50 = 36 nM at the SlP(4) receptor using a [gamma-S-35]GTP binding assay as compared to an EC50 = 37 nM for the endogenous ligand. We also report the effects of altering stereochemistry at the C2 position, methylation at the C1 and C2 position, and activity differences between the alcohol and phosphate head groups of the analogues. (C) 2004 Elsevier Ltd. All rights reserved.