1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl) (methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol | 956507-49-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl) (methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol
• 英文别名: 1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl)(methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol；T5342126；1-[[1-[(2-Chlorophenyl)methyl]-3,5-dimethylpyrazol-4-yl]methyl-methylamino]-3-(4-ethoxyphenoxy)propan-2-ol
• CAS: 956507-49-6
• 化学式: C₂₅H₃₂ClN₃O₃
• 分子量: 458.0
• InChiKey: UOKIJOWYTBNPIM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  32
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  59.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl) (methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol 、 碘甲烷 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 0.67h， 以37%的产率得到N-((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-methyl)-3-(4-ethoxyphenoxy)-2-methoxy-N-methylpropan-1-amine
  参考文献：
  名称：

  Development of β-Amino Alcohol Derivatives That Inhibit Toll-like Receptor 4 Mediated Inflammatory Response as Potential Antiseptics

  摘要：

  Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of beta-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.

  DOI：

  10.1021/jm2003365
• 作为产物：
  描述：

  4-乙氧基苯酚 在 potassium carbonate 作用下， 以 丙酮 、 乙腈 为溶剂， 反应 72.0h， 生成 1-(((1-(2-chlorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)methyl) (methyl)amino)-3-(4-ethoxyphenoxy)propan-2-ol
  参考文献：
  名称：

  Development of β-Amino Alcohol Derivatives That Inhibit Toll-like Receptor 4 Mediated Inflammatory Response as Potential Antiseptics

  摘要：

  Toll-like receptor 4 (TLR4) induced proinflammatory signaling has been directly implicated in severe sepsis and represents an attractive therapeutic target. Herein, we report our investigations into the structure-activity relationship and preliminary drug metabolism/pharmacokinetics study of beta-amino alcohol derivatives that inhibit the TLR4 signaling pathway. Lead compounds were identified from in vitro cellular examination with micromolar potency for their inhibitory effects on TLR4 signaling and subsequently assessed for their ability to suppress the TLR4-induced inflammatory response in an ex vivo whole blood model. In addition, the toxicology, specificity, solubility, brain-blood barrier permeability, and drug metabolism of several compounds were evaluated. Although further optimizations are needed, our findings lay the groundwork for the future drug development of this class of small molecule agents for the treatment of severe sepsis.

  DOI：

  10.1021/jm2003365

文献信息

• Method for Treating Scleroderma
  申请人：The Regents of the University of Colorado, A body corporate

  公开号：US20150087682A1

  公开（公告）日：2015-03-26

  The present invention provides a method for treating scleroderma by administering a therapeutically effective amount of a toll like receptor 4 inhibitor to a subject in need of such a treatment.

  本发明提供了一种治疗硬皮病的方法，通过向需要此类治疗的受试者施用治疗有效量的Toll样受体4抑制剂。
• TOLL-LIKE RECEPTOR MODULATORS AND USES THEREOF
  申请人：Yin Hang

  公开号：US20120178774A1

  公开（公告）日：2012-07-12

  The present invention provides a compound selected from the group consisting of: where n, m, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3 , R 11 , R 12 , Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are those defined herein. Some aspects of the invention also provides methods for using these compounds and compositions comprising the same.

  本发明提供了从以下组中选择的化合物：其中n，m，X1，X2，X3，X4，R1，R2，R3，R11，R12，Y1，Y2，Y3，Y4和Y5如本文所定义。本发明的某些方面还提供了使用这些化合物的方法和包含它们的组合物。
• Toll-like receptor modulators and uses thereof
  申请人：Yin Hang

  公开号：US08642614B2

  公开（公告）日：2014-02-04

  The present invention provides a compound of the formula: where n, m, X1, X2, X3, X4, R1, R2 and R3 are those defined herein. Some aspects of the invention also provides methods for using these compounds and compositions comprising the same.

  本发明提供了一个化合物的公式：其中n，m，X1，X2，X3，X4，R1，R2和R3如本文所定义。本发明的某些方面还提供了使用这些化合物的方法和包含相同化合物的组合物。
• Discovery of novel small molecule TLR4 inhibitors as potent anti-inflammatory agents
  作者：Yao Xu、Shujun Chen、Ying Cao、Pingzheng Zhou、Zhipeng Chen、Kui Cheng

  DOI：10.1016/j.ejmech.2018.05.033

  日期：2018.6

  Toll-like receptor 4 (TLR4) initiates innate immune response to release inflammatory cytokines and has been pathologically linked to variety of inflammatory diseases. Recently, we found that Carvedilol, as the classic anti-heart failure and anti-inflammatory clinic drug, could inhibit the TLR4 signaling in the TLR4 overexpressed cells. Herein, we have designed and synthesized a small library of novel Carvedilol derivatives and investigated their potential inhibitory activity. The results indicate that the most potent compound 8a (SMU-XY3) could effectively inhibited TLR4 protein and the LPS triggered alkaline phosphatase signaling in HEK-Blue hTLR4 cells. It down regulated the nitric oxide (NO) in both RAW264.7 cells and BV-2 microglial cells, in addition to blocking the TNF-alpha signaling in ex-vivo human peripheral blood mononuclear cells (PBMC). More interestingly, 8a shows higher affinity to hyperpolarization-activated cyclic nucleotide-gated 4 (HCN4) over HCN2, which probably indicates the new application of TLR4 inhibitor 8a in heart failure, coronary heart disease, and other inflammatory diseases. (C) 2018 Elsevier Masson SAS. All rights reserved.
• Selection, Preparation, and Evaluation of Small-Molecule Inhibitors of Toll-Like Receptor 4
  作者：Douglas E. Bevan、Alexander J. Martinko、Lisa C. Loram、Joshua A. Stahl、Frederick R. Taylor、Sampada Joshee、Linda R. Watkins、Hang Yin

  DOI：10.1021/ml100041f

  日期：2010.8.12

  Toll-like receptor 4 (TLR4), a membrane-spanning receptor protein that functions in complex with its accessory protein MD-2, is an intriguing target for therapeutic development. Herein, we report the identification of a series of novel TLR4 inhibitors and the development of a robust, enantioselective synthesis using an unprecedented Mannich type reaction to functionalize a pyrazole ring. In silico and cellular assay results demonstrated that compound 1 and its analogues selectively block TLR4 activation in live cells. Animal model tests showed that 1 and its derivatives could potentiate morphine-induced analgesia in vivo, presumably by attenuating the opioid-induced TLR4 activation.