1,1-dimethylethyl (2-{[5-(trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)carbamate | 1207192-88-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1,1-dimethylethyl (2-{[5-(trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)carbamate
• 英文别名: tert-butyl N-[2-[5-(trifluoromethyl)pyridin-2-yl]sulfonylethyl]carbamate
• CAS: 1207192-88-8
• 化学式: C₁₃H₁₇F₃N₂O₄S
• 分子量: 354.35
• InChiKey: GUTFBXQUTOJJGQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  23
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  93.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl (2-{[5-(trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)carbamate 在 盐酸 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 50.42h， 生成 N-(2-((5-(trifluoromethyl)pyridin-2-yl)sulfonyl)ethyl)quinoline-8-carboxamide
  参考文献：
  名称：

  Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ

  摘要：

  The covalent modification of peroxisome-proliferator activated receptor beta/delta (PPAR beta/delta) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPAR beta/delta antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPAR beta/delta is achievable at the expense of their immediate affinity for PPAR beta/delta. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.12.012
• 作为产物：
  描述：

  2-巯基-5-(三氟甲基)吡啶 在 Oxone 、 三乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 42.0h， 生成 1,1-dimethylethyl (2-{[5-(trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)carbamate
  参考文献：
  名称：

  Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ

  摘要：

  The covalent modification of peroxisome-proliferator activated receptor beta/delta (PPAR beta/delta) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPAR beta/delta antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPAR beta/delta is achievable at the expense of their immediate affinity for PPAR beta/delta. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.12.012

文献信息

• Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARα
  作者：H. Eric Xu、Thomas B. Stanley、Valerie G. Montana、Millard H. Lambert、Barry G. Shearer、Jeffery E. Cobb、David D. McKee、Cristin M. Galardi、Kelli D. Plunket、Robert T. Nolte、Derek J. Parks、John T. Moore、Steven A. Kliewer、Timothy M. Willson、Julie B. Stimmel

  DOI：10.1038/415813a

  日期：2002.2

  Repression of gene transcription by nuclear receptors is mediated by interactions with co-repressor proteins such as SMRT and N-CoR1,2, which in turn recruit histone deacetylases to the chromatin3,4,5. Aberrant interactions between nuclear receptors and co-repressors contribute towards acute promyelocytic leukaemia and thyroid hormone resistance syndrome6,7,8. The binding of co-repressors to nuclear receptors occurs in the unliganded state, and can be stabilized by antagonists9. Here we report the crystal structure of a ternary complex containing the peroxisome proliferator-activated receptor-α ligand-binding domain bound to the antagonist GW6471 and a SMRT co-repressor motif. In this structure, the co-repressor motif adopts a three-turn α-helix that prevents the carboxy-terminal activation helix (AF-2) of the receptor from assuming the active conformation. Binding of the co-repressor motif is further reinforced by the antagonist, which blocks the AF-2 helix from adopting the active position. Biochemical analyses and structure-based mutagenesis indicate that this mode of co-repressor binding is highly conserved across nuclear receptors.

  核受体对基因转录的抑制是通过与共同抑制蛋白（如SMRT和N-CoR）相互作用来介导的，这些共同抑制蛋白反过来招募组蛋白去乙酰化酶到染色质上。核受体和共同抑制因子之间的异常相互作用与急性早幼粒细胞白血病和甲状腺激素抵抗综合症有关。共同抑制因子与核受体的结合发生在未结合配体的状态，并可被拮抗剂稳定。在这里，我们报告了一种三元复合物的晶体结构，该复合物包含过氧化物酶体增殖物激活受体-α的配体结合域，与拮抗剂GW6471和SMRT共同抑制基序结合。在这个结构中，共同抑制基序呈现出一个三圈的α-螺旋，阻止受体的羧基末端激活螺旋（AF-2）呈现活性构象。拮抗剂进一步增强了共同抑制基序的结合，阻止AF-2螺旋采纳主动位置。生化分析和基于结构的突变实验表明，这种共同抑制基序的结合模式在核受体中高度保守。
• Identification and Characterization of 4-Chloro-<i>N</i>-(2-{[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide (GSK3787), a Selective and Irreversible Peroxisome Proliferator-Activated Receptor δ (PPARδ) Antagonist
  作者：Barry G. Shearer、Robert W. Wiethe、Adam Ashe、Andrew N. Billin、James M. Way、Thomas B. Stanley、Craig D. Wagner、Robert X. Xu、Lisa M. Leesnitzer、Raymond V. Merrihew、Todd W. Shearer、Michael R. Jeune、John C. Ulrich、Timothy M. Willson

  DOI：10.1021/jm900464j

  日期：2010.2.25

  4-Chloro-N-(2-[5-trifluoromethyl)-2-pyridyl]sulfonyl}ethyl)benzamide 3 (GSK3787) was identified as a potent and selective ligand for PPAR delta wish good pharmacokinetic properties. A detailed binding study using mass spectral analysis confirmed covalent binding to Cys249 within the PPAR delta binding pocket. Gene expression studies showed that pyridylsulfone 3 antagonized the transcriptional activity of PPAR delta and inhibited basal CPT1a gene transcription. Compound 3 is a PPAR delta antagonist with utility as it tool to elucidate PPAR delta cell biology and pharmacology.
• Synthesis of 5-trifluoromethyl-2-sulfonylpyridine PPARβ/δ antagonists: Effects on the affinity and selectivity towards PPARβ/δ
  作者：Åsmund Kaupang、Eili Tranheim Kase、Cecilie Xuan Trang Vo、Marthe Amundsen、Anders Vik、Trond Vidar Hansen

  DOI：10.1016/j.bmc.2015.12.012

  日期：2016.1

  The covalent modification of peroxisome-proliferator activated receptor beta/delta (PPAR beta/delta) is part of the mode of action of 5-trifluoromethyl-2-sulfonylpyridine PPAR beta/delta antagonists such as GSK3787 and CC618. Herein, the synthesis and in vitro biological evaluation of a range of structural analogues of the two antagonists are reported. The new ligands demonstrate that an improvement in the selectivity of 5-trifluoromethyl-2-sulfonylpyridine antagonists towards PPAR beta/delta is achievable at the expense of their immediate affinity for PPAR beta/delta. However, their putatively covalent and irreversible mode of action may ensure their efficacy over time, as observed in time-resolved fluorescence resonance energy transfer (TR-FRET)-based ligand displacement assays. (c) 2015 Elsevier Ltd. All rights reserved.