(S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)methaniminium 2,2,2-trifluoroacetate

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)methaniminium 2,2,2-trifluoroacetate
• 英文别名: (S)-2-((4-octylbenzamido)methyl)pyrrolidin-1-ium 2,2,2-trifluoroacetate；N-[[(2S)-1-carbamimidoylpyrrolidin-2-yl]methyl]-4-octylbenzamide;2,2,2-trifluoroacetic acid
• 化学式: C₂HF₃O₂*C₂₁H₃₄N₄O
• 分子量: 472.551
• InChiKey: AQYPATXXBYHLLY-FYZYNONXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.31
• 重原子数：
  33
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  120
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-正辛基苯甲酸 在 N-羟基丁二酰亚胺 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 反应 6.0h， 生成 (S)-amino(2-((4-octylbenzamido)methyl)pyrrolidin-1-yl)methaniminium 2,2,2-trifluoroacetate
  参考文献：
  名称：

  Structure−Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1- and SphK2-Selective Inhibitors

  摘要：

  Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P(1-5)) 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 (K-i = 1 mu M), 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 (K-i = 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.

  DOI：

  10.1021/jm501760d

文献信息

• Structure−Activity Relationship Studies and in Vivo Activity of Guanidine-Based Sphingosine Kinase Inhibitors: Discovery of SphK1- and SphK2-Selective Inhibitors
  作者：Neeraj N. Patwardhan、Emily A. Morris、Yugesh Kharel、Mithun R. Raje、Ming Gao、Jose L. Tomsig、Kevin R. Lynch、Webster L. Santos

  DOI：10.1021/jm501760d

  日期：2015.2.26

  Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that acts as a ligand for five G-protein coupled receptors (S1P(1-5)) 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 (K-i = 1 mu M), 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 (K-i = 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.