JNJ-40355003 | 1394894-41-7

• 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: JNJ-40355003
• 英文别名: 4-({3-[(4-chlorophenyl)oxy]phenyl}methyl)-N-pyridin-3-ylpiperazine-1-carboxamide；1-Piperazinecarboxamide, 4-((3-(4-chlorophenoxy)phenyl)methyl)-N-3-pyridinyl-；4-[[3-(4-chlorophenoxy)phenyl]methyl]-N-pyridin-3-ylpiperazine-1-carboxamide
• CAS: 1394894-41-7
• 化学式: C₂₃H₂₃ClN₄O₂
• 分子量: 422.914
• InChiKey: CTYVKSQPMCSUOR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  57.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-(4-氯苯氧基)苯甲醛 在 盐酸 、 三乙酰氧基硼氢化钠 、 三乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 23.0h， 生成 JNJ-40355003
  参考文献：
  名称：

  The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors

  摘要：

  The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4: 1 to as low as 0.02: 1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (V-d) obtained from pharmacokinetic (PK) experiments as very high V(d)s did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.05.001

文献信息

• [EN] PIPERAZINECARBOXAMIDE DERIVATIVE USEFUL AS A MODULATOR OF FATTY ACID AMIDE HYDROLASE (FAAH)<br/>[FR] DÉRIVÉ DE PIPÉRAZINE-CARBOXAMIDE UTILE EN TANT QUE MODULATEUR DE LA FAAH (FATTY ACID AMIDE HYDROLASE)
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2011060026A1

  公开（公告）日：2011-05-19

  N-Pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1- carboxamide is described, which is useful as a FAAH inhibitor. N-Pyridin-3-yl- 4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). A method of synthesizing N-pyridin-3-yl-4-3-[4- (trifluoromethyl)phenoxy]benzyl}piperazine-1 -carboxamide is also disclosed.

  本文介绍了一种名为N-Pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide的物质，它可用作FAAH抑制剂。N-Pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide可用于制备药物组合物和治疗由脂肪酰胺水解酶（FAAH）活性介导的疾病状态、失调和症状，如焦虑、疼痛、炎症、睡眠障碍、进食障碍、能量代谢障碍和运动障碍（如多发性硬化症）的方法。本文还公开了一种合成N-pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide的方法。
• PIPERAZINECARBOXAMIDE DERIVATIVE USEFUL AS A MODULATOR OF FATTY ACID AMIDE HYDROLASE (FAAH)
  申请人：Hawryluk Natalie A.

  公开号：US20120225097A1

  公开（公告）日：2012-09-06

  N-Pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide is described, which is useful as a FAAH inhibitor. N-Pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, energy metabolism disorders, and movement disorders (e.g., multiple sclerosis). A method of synthesizing N-pyridin-3-yl-4-3-[4-(trifluoromethyl)phenoxy]benzyl}piperazine-1-carboxamide is also disclosed.

  本文介绍了一种名为N-Pyridin-3-yl-4-3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-羧酰胺的物质，它可用作FAAH（脂肪酸酰胺水解酶）抑制剂。N-Pyridin-3-yl-4-3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-羧酰胺可用于制备药物组合物和治疗由FAAH活性介导的疾病状态、疾患和症状，例如焦虑、疼痛、炎症、睡眠障碍、饮食障碍、能量代谢障碍和运动障碍（如多发性硬化）。本文还公开了一种合成N-pyridin-3-yl-4-3-[4-(三氟甲基)苯氧基]苄基}哌嗪-1-羧酰胺的方法。
• Aryl Piperazinyl Ureas as Inhibitors of Fatty Acid Amide Hydrolase (FAAH) in Rat, Dog, and Primate
  作者：John M. Keith、Rich Apodaca、Mark Tichenor、Wei Xiao、William Jones、Joan Pierce、Mark Seierstad、James Palmer、Michael Webb、Mark Karbarz、Brian Scott、Sandy Wilson、Lin Luo、Michelle Wennerholm、Leon Chang、Sean Brown、Michele Rizzolio、Raymond Rynberg、Sandra Chaplan、J. Guy Breitenbucher

  DOI：10.1021/ml300186g

  日期：2012.10.11

  A series of aryl piperazinyl ureas that act as covalent inhibitors of fatty acid amide hydrolase (FAAH) is described. A potent and selective (does not inhibit FAAH-2) member of this class, JNJ-40355003, was found to elevate the plasma levels of three fatty acid amides: anandamide, oleoyl ethanolamide, and palmitoyl ethanolamide, in the rat, dog, and cynomolgous monkey. The elevation of the levels of these lipids in the plasma of monkeys suggests that FAAH-2 may not play a significant role in regulating plasma levels of fatty acid ethanolamides in primates.
• The SAR of brain penetration for a series of heteroaryl urea FAAH inhibitors
  作者：John M. Keith、Mark S. Tichenor、Richard L. Apodaca、Wei Xiao、William M. Jones、Mark Seierstad、Joan M. Pierce、James A. Palmer、Michael Webb、Mark J. Karbarz、Brian P. Scott、Sandy J. Wilson、Michelle L. Wennerholm、Michele Rizzolio、Raymond Rynberg、Sandra R. Chaplan、J. Guy Breitenbucher

  DOI：10.1016/j.bmcl.2016.05.001

  日期：2016.7

  The SAR of brain penetration for a series of heteroaryl piperazinyl- and piperadinyl-urea fatty acid amide hydrolase (FAAH) inhibitors is described. Brain/plasma (B/P) ratios ranging from >4: 1 to as low as 0.02: 1 were obtained through relatively simple structural changes to various regions of the heteroaryl urea scaffold. It was not possible to predict the degree of central nervous system (CNS) penetration from the volumes of distribution (V-d) obtained from pharmacokinetic (PK) experiments as very high V(d)s did not correlate with high B/P ratios. Similarly, calculated topological polar surface areas (TPSAs) did not consistently correlate with the degree of brain penetration. The lowest B/P ratios were observed for those compounds that were significantly ionized at physiological pH. However, as this class of compounds inhibits the FAAH enzyme through covalent modification, low B/P ratios did not preclude effective central target engagement. (C) 2016 Elsevier Ltd. All rights reserved.