(4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone

• 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: (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone
• 英文别名: (4-[4-chlorobenzoyl]piperidin-1-yl)(4-methoxyphenyl)methanone；ASN 06583334；CL6a；(4-Chlorophenyl)-[1-(4-methoxybenzoyl)piperidin-4-yl]methanone
• 化学式: C₂₀H₂₀ClNO₃
• 分子量: 357.837
• InChiKey: UXQGJOGBIHMDHQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以69%的产率得到(4-(4-chlorobenzoyl)piperidin-1-yl)(4-hydroxyphenyl)methanone
  参考文献：
  名称：

  用于开发有效，可逆和选择性单酰基甘油脂肪酶（MAGL）抑制剂的4-氯苯甲酰基哌啶衍生物的结构优化

  摘要：

  单酰基甘油脂肪酶（MAGL）抑制剂被认为是各种病理状况（包括几种癌症）的潜在治疗剂。文献中报道了许多MAGL抑制剂。然而，它们大多数显示出不可逆的作用机理，这引起了重要的副作用。迄今为止，可逆的MAGL抑制剂的使用仅得到了部分研究，这主要是由于缺乏具有良好的MAGL可逆抑制特性的化合物。在这项研究中，我们从显示可逆的MAGL抑制机制（K i = 8.6μM）的（4-（4-氯苯甲酰基）哌啶-1-基）（4-甲氧基苯基）甲酮（CL6a）铅化合物开始，我们开始对其结构进行优化，我们开发了一种新的高效选择性MAGL抑制剂（17b，K i = 0.65μM）。此外，建模研究表明，该化合物的结合相互作用取代了在MAGL结合位点复制其H键的结构水分子，从而为开发新的MAGL抑制剂确定了新的关键锚点。

  DOI：

  10.1021/acs.jmedchem.6b01459
• 作为产物：
  描述：

  4-(4-氯苯甲酰基)哌啶 、 大茴香酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 以57%的产率得到(4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone
  参考文献：
  名称：

  Identification and characterization of a new reversible MAGL inhibitor

  摘要：

  Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yI)(4-methoxyPhenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (K-i=8.6 mu M), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.04.057

文献信息

• METHODS OF TREATING RENAL DISEASE
  申请人：The Regents of the University of California

  公开号：EP3823610A1

  公开（公告）日：2021-05-26
• [EN] METHODS OF TREATING RENAL DISEASE<br/>[FR] MÉTHODES DE TRAITEMENT D'UNE MALADIE RÉNALE
  申请人：UNIV CALIFORNIA

  公开号：WO2020018554A1

  公开（公告）日：2020-01-23

  Disclosed herein, inter alia, are methods of treating renal disease (e.g., chronic kidney disease or end stage renal disease).
• Structural Optimization of 4-Chlorobenzoylpiperidine Derivatives for the Development of Potent, Reversible, and Selective Monoacylglycerol Lipase (MAGL) Inhibitors
  作者：Carlotta Granchi、Flavio Rizzolio、Stefano Palazzolo、Sara Carmignani、Marco Macchia、Giuseppe Saccomanni、Clementina Manera、Adriano Martinelli、Filippo Minutolo、Tiziano Tuccinardi

  DOI：10.1021/acs.jmedchem.6b01459

  日期：2016.11.23

  we started its structural optimization and we developed a new potent and selective MAGL inhibitor (17b, Ki = 0.65 μM). Furthermore, modeling studies suggested that the binding interactions of this compound replace a structural water molecule reproducing its H-bonds in the MAGL binding site, thus identifying a new key anchoring point for the development of new MAGL inhibitors.

  单酰基甘油脂肪酶（MAGL）抑制剂被认为是各种病理状况（包括几种癌症）的潜在治疗剂。文献中报道了许多MAGL抑制剂。然而，它们大多数显示出不可逆的作用机理，这引起了重要的副作用。迄今为止，可逆的MAGL抑制剂的使用仅得到了部分研究，这主要是由于缺乏具有良好的MAGL可逆抑制特性的化合物。在这项研究中，我们从显示可逆的MAGL抑制机制（K i = 8.6μM）的（4-（4-氯苯甲酰基）哌啶-1-基）（4-甲氧基苯基）甲酮（CL6a）铅化合物开始，我们开始对其结构进行优化，我们开发了一种新的高效选择性MAGL抑制剂（17b，K i = 0.65μM）。此外，建模研究表明，该化合物的结合相互作用取代了在MAGL结合位点复制其H键的结构水分子，从而为开发新的MAGL抑制剂确定了新的关键锚点。
• Identification and characterization of a new reversible MAGL inhibitor
  作者：Tiziano Tuccinardi、Carlotta Granchi、Flavio Rizzolio、Isabella Caligiuri、Vittoria Battistello、Giuseppe Toffoli、Filippo Minutolo、Marco Macchia、Adriano Martinelli

  DOI：10.1016/j.bmc.2014.04.057

  日期：2014.7

  Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yI)(4-methoxyPhenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (K-i=8.6 mu M), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases. (C) 2014 Elsevier Ltd. All rights reserved.