CYM-5473 | 851285-84-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: CYM-5473
• 英文别名: 1-[2-(2,5-Dimethyl-1-phenylpyrrol-3-yl)-2-oxoethyl]-5-(trifluoromethyl)pyridin-2-one
• CAS: 851285-84-2
• 化学式: C₂₀H₁₇F₃N₂O₂
• 分子量: 374.362
• InChiKey: BMOILWUSXRRCJC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  42.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氯-1-(2,5-二甲基-1-苯基-1H-吡咯-3-基)-1-乙酮 、 2-羟基-5-三氟甲基吡啶 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 以34%的产率得到CYM-5473
  参考文献：
  名称：

  A sphingosine 1-phosphate receptor 2 selective allosteric agonist

  摘要：

  Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-kappa B-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other SIP receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with SIP is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.012

文献信息

• A sphingosine 1-phosphate receptor 2 selective allosteric agonist
  作者：Hideo Satsu、Marie-Therese Schaeffer、Miguel Guerrero、Adrian Saldana、Christina Eberhart、Peter Hodder、Charmagne Cayanan、Stephan Schürer、Barun Bhhatarai、Ed Roberts、Hugh Rosen、Steven J. Brown

  DOI：10.1016/j.bmc.2013.06.012

  日期：2013.9

  Molecular probe tool compounds for the Sphingosine 1-phosphate receptor 2 (S1PR2) are important for investigating the multiple biological processes in which the S1PR2 receptor has been implicated. Amongst these are NF-kappa B-mediated tumor cell survival and fibroblast chemotaxis to fibronectin. Here we report our efforts to identify selective chemical probes for S1PR2 and their characterization. We employed high throughput screening to identify two compounds which activate the S1PR2 receptor. SAR optimization led to compounds with high nanomolar potency. These compounds, XAX-162 and CYM-5520, are highly selective and do not activate other SIP receptors. Binding of CYM-5520 is not competitive with the antagonist JTE-013. Mutation of receptor residues responsible for binding to the zwitterionic headgroup of sphingosine 1-phosphate (S1P) abolishes S1P activation of the receptor, but not activation by CYM-5520. Competitive binding experiments with radiolabeled S1P demonstrate that CYM-5520 is an allosteric agonist and does not displace the native ligand. Computational modeling suggests that CYM-5520 binds lower in the orthosteric binding pocket, and that co-binding with SIP is energetically well tolerated. In summary, we have identified an allosteric S1PR2 selective agonist compound. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.