trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid

• 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: trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid
• 英文别名: t-AUCB；4-[[trans-4-[[(tricyclo[3.3.1 1³_'⁷]dec-1-ylamino)carbonyl]amino]cyclohexyl]oxy]benzoic acid；4-(((1r,4r)-4-(3-(adamantan-1-yl)ureido)cyclohexyl)oxy)benzoic acid；trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid；trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxyl]-benzoic acid；trans-4-[4-(3-adamantan-1-ylureido)-cyclohexyloxy]-benzoic acid
• 化学式: C₂₄H₃₂N₂O₄
• 分子量: 412.529
• InChiKey: KNBWKJBQDAQARU-KSSCSKLYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.34
• 重原子数：
  30.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  87.66
• 氢给体数：
  3.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid 、 甲胺 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 以85%的产率得到trans-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]-N-methylbenzamide
  参考文献：
  名称：

  [EN] SORAFENIB DERIVATIVES AS sEH INHIBITORS
  [FR] DÉRIVÉS DE SORAFÉNIB UTILISÉS EN TANT QU'INHIBITEURS DE LA SEH

  摘要：

  本发明提供了用于抑制可溶性环氧化物水解酶及相关疾病状况的化合物。

  公开号：

  WO2012112570A1
• 作为产物：
  描述：

  trans-4-Aminocyclohexanol 在 sodium hydride 、 三乙胺 、 sodium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 37.0h， 生成 trans-4-[4-(3-adamantan-1-ylureido)cyclohexyloxy]benzoic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of sorafenib- and regorafenib-like sEH inhibitors

  摘要：

  To reduce the pro-angiogenic effects of sEH inhibition, a structure-activity relationship (SAR) study was performed by incorporating structural features of the anti-angiogenic multi-kinase inhibitor sorafenib into soluble epoxide hydrolase (sEH) inhibitors. The structural modifications of this series of molecules enabled the altering of selectivity towards the pro-angiogenic kinases C-RAF and vascular endothelial growth factor receptor-2 (VEGFR-2), while retaining their sEH inhibition. As a result, sEH inhibitors with greater potency against C-RAF and VEGFR-2 were obtained. Compound 4 (t-CUPM) possesses inhibition potency higher than sorafenib towards sEH but similar against C-RAF and VEGFR-2. Compound 7 (t-CUCB) selectively inhibits sEH, while inhibiting HUVEC cell proliferation, a potential anti-angiogenic property, without liver cancer cell cytotoxicity. The data presented suggest a potential rational approach to control the angiogenic responses stemming from sEH inhibition. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.011

文献信息

• PYRAZOLE INHIBITORS OF COX-2 AND SEH
  申请人：Hammock Bruce D.

  公开号：US20140038923A1

  公开（公告）日：2014-02-06

  The present invention provides compounds and compositions, e.g., a series of compounds wherein a 1,5-biarylpyrazole group is conjugated to a urea group by a non-cleavable covalent chain, that are useful as dual COX-2/sEH inhibitors. The compounds disclosed herein have activity associated with the arachidonate cascade. The activity of these compounds was demonstrated using a lipopolysaccharide (LPS) induced model of pain in the rat. The compounds of the present invention demonstrated superior anti-allodynic activity as compared to the same dose of celecoxib, i.e., a COX-2 inhibitor, also as compared to the same dose of t-AUCB, i.e., a sEH inhibitor, and also as compared to the co-administered same dose of both celecoxib and t-AUCB. The dual inhibitors of the present invention demonstrate enhanced in vivo anti-allodynic activity in a nociceptive behavioral assay. In addition, the compounds of the present invention also demonstrated to have potent anti-angiogenic effects toward endothelial cells (HUVEC) and inhibit angiogenesis in vitro, ex vivo and in vivo. The dual inhibitors of the present invention also demonstrate anti-angiogenic effect to slow breast tumor growth in vivo.

  本发明提供了化合物和组合物，例如一系列化合物，其中1,5-联苯吡唑基通过不可断裂的共价链与尿素基结合，这些化合物可用作双COX-2/sEH抑制剂。本文披露的化合物具有与花生四烯酸级联相关的活性。这些化合物的活性是使用大鼠脂多糖（LPS）诱导的疼痛模型进行证明的。与同等剂量的Celecoxib（即COX-2抑制剂）以及同等剂量的t-AUCB（即sEH抑制剂）相比，本发明的化合物表现出优越的抗痛觉过敏活性，也与同时给予的Celecoxib和t-AUCB的同等剂量相比。本发明的双重抑制剂在伤害性行为测定中显示出增强的体内抗痛觉过敏活性。此外，本发明的化合物还表现出对内皮细胞（HUVEC）具有强效的抗血管生成作用，并且在体外、体内和体内抑制血管生成。本发明的双重抑制剂还表现出抗血管生成效应，可以减缓体内乳腺肿瘤生长。
• Identification and optimization of soluble epoxide hydrolase inhibitors with dual potency towards fatty acid amide hydrolase
  作者：Sean D. Kodani、Saavan Bhakta、Sung Hee Hwang、Svetlana Pakhomova、Marcia E. Newcomer、Christophe Morisseau、Bruce D. Hammock

  DOI：10.1016/j.bmcl.2018.01.003

  日期：2018.2

  competitive mechanism. These inhibitors are selective for FAAH over other serine hydrolases. In addition, FAAH inhibition by t-TUCB appears to be higher in human FAAH over other species; however, the new dual sEH/FAAH inhibitors have improved cross-species potency. These dual inhibitors may be useful for future studies in understanding the therapeutic application of dual sEH/FAAH inhibition.

  作为利用多药理学优势同时简化药物输送的一种手段，多靶点抑制剂已变得越来越流行。在这里，我们描述了可溶性环氧化物水解酶（sEH）和脂肪酸酰胺水解酶（FAAH）的两种抑制剂，这两种抑制剂在治疗炎症性疼痛和神经性疼痛时已知具有协同作用。本文所述的结构活性关系（SAR）研究最初始于t -TUCB（trans-4- [4-（4-（3-三氟甲氧基苯基-1-脲基）-环己氧基]-苯甲酸），一种有效的sEH抑制剂，先前已显示出弱抑制FAAH的作用。通过优化开发了在维持高sEH效能的同时，将FAAH效能提高6倍的抑制剂。有趣的是，与大多数通过时间依赖性共价修饰抑制的FAAH抑制剂相比，t -TUCB和相关化合物似乎通过时间依赖性竞争机制抑制FAAH。这些抑制剂对FAAH的选择性高于其他丝氨酸水解酶。另外，FAAH对t的抑制作用-TUCB在人类FAAH中似乎比其他物种更高；然而，新型的双重sEH / FAAH抑
• [EN] PREPARATION OF NOVEL 1,3-SUBSTITUTED UREAS AS INHIBITORS OF SOLUBLE EPOXIDE HYDROLASE<br/>[FR] PRÉPARATION D'URÉES 1,3-SUBSTITUÉES NOVATRICES EN TANT QU'INHIBITEURS D'ÉPOXYDE HYDROLASE SOLUBLE
  申请人：UNIV CALIFORNIA

  公开号：WO2009020960A1

  公开（公告）日：2009-02-12

  The present invention provides compounds that can inhibit the activity of soluble epoxide hydrolases. In particular, the present invention provides compounds of Formula (I).

  本发明提供了一种可以抑制可溶性环氧酶活性的化合物。特别地，本发明提供了式（I）的化合物。
• SORAFENIB DERIVATIVES AS SEH INHIBITORS
  申请人：Hammock Bruce D.

  公开号：US20140088156A1

  公开（公告）日：2014-03-27

  The present invention provides compounds for the inhibition of soluble epoxide hydrolase and associated disease conditions.

  本发明提供了用于抑制可溶性环氧酰胺酶及相关疾病状况的化合物。
• Inhibitors for the Soluble Epoxide Hydrolase
  申请人：HAMMOCK BRUCE D.

  公开号：US20110021448A1

  公开（公告）日：2011-01-27

  Inhibitors of the soluble epoxide hydrolase (sEH) are provided that incorporate multiple pharmacophores and are useful in the treatment of diseases.

  提供了可用于治疗疾病的可溶性环氧酶（sEH）抑制剂，其中包含多个药效团。