N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)-4-(bromo)benzamide

• 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: N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)-4-(bromo)benzamide
• 英文别名: 4-bromo-N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)benzamide；4-bromo-N-[5-(2,3-dihydro-1,4-benzodioxin-6-yl)-1,3,4-oxadiazol-2-yl]benzamide
• 化学式: C₁₇H₁₂BrN₃O₄
• 分子量: 402.204
• InChiKey: ZXDCZNWXQFSKGR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  86.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  (E)-2-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methylene)hydrazine-1-carboxamide 在 吡啶 、 sodium acetate 、 溶剂黄146 作用下， 反应 19.0h， 生成 N-(5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,3,4-oxadiazol-2-yl)-4-(bromo)benzamide
  参考文献：
  名称：

  Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain

  摘要：

  Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1 /AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 CAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.11.036

文献信息

• ADENYLYL CYCLASE INHIBITORS FOR CHRONIC PAIN AND OPIOID DEPENDENCE
  申请人：Purdue Research Foundation

  公开号：US20190002418A1

  公开（公告）日：2019-01-03

  This present application disclosed a series of selective adenylyl cyclase 1 (AC1) inhibitors as a pain therapeutic. Those compounds may provide an effective method of treatment for chronic/inflammatory pain. Those compounds may also prevent opioid dependence and/or reduce opioid dependence. Both method and composition matters are within the scope of this invention.

  本申请公开了一系列选择性腺苷酸环化酶1（AC1）抑制剂作为疼痛治疗的药物。这些化合物可能提供一种有效的治疗慢性/炎性疼痛的方法。这些化合物还可以预防阿片类药物依赖和/或减少阿片类药物依赖。该发明涉及方法和组合物两个方面。
• Adenylyl cyclase inhibitors for chronic pain and opioid dependence
  申请人：Purdue Research Foundation

  公开号：US10457653B2

  公开（公告）日：2019-10-29

  This present application disclosed a series of selective adenylyl cyclase 1 (AC1) inhibitors, compounds having a formula or a pharmaceutically acceptable salt thereof, as a pain therapeutic. Those compounds may provide an effective method of treatment for chronic/inflammatory pain. Those compounds may also prevent opioid dependence and/or reduce opioid dependence. Both method and composition matters are within the scope of this invention.

  本申请公开了一系列选择性腺苷酸环化酶 1（AC1）抑制剂，这些化合物的化学式为 或其药学上可接受的盐，作为疼痛治疗剂。这些化合物可为慢性/炎症性疼痛提供有效的治疗方法。这些化合物还可以预防阿片类药物依赖和/或减少阿片类药物依赖。方法和组合物均属于本发明的范围。
• METHODS FOR TREATING CHRONIC PAIN AND OPIOID DEPENDENCE USING ADENYLYL CYCLASE INHIBITORS
  申请人：Purdue Research Foundation

  公开号：US20200031785A1

  公开（公告）日：2020-01-30

  This present application disclosed a method for the treatment of treating pain, opioid dependence, alcohol use disorder or autism comprising the step of administering to a mammal in need thereof a therapeutically effective amount of one or more compounds of formula (I), or a pharmaceutically acceptable salt thereof, and one or more carriers, diluents, or excipients. Those compounds are selective adenylyl cyclase 1 (AC1) inhibitors, which may provide an effective method of treatment for chronic/inflammatory pain, and prevent opioid dependence and/or reduce opioid dependence.
• Optimization of a 1,3,4-oxadiazole series for inhibition of Ca2+/calmodulin-stimulated activity of adenylyl cyclases 1 and 8 for the treatment of chronic pain
  作者：Jatinder Kaur、Monica Soto-Velasquez、Zhong Ding、Ahmadreza Ghanbarpour、Markus A. Lill、Richard M. van Rijn、Val J. Watts、Daniel P. Flaherty

  DOI：10.1016/j.ejmech.2018.11.036

  日期：2019.1

  Adenylyl cyclases type 1 (AC1) and 8 (AC8) are group 1 transmembrane adenylyl cyclases (AC) that are stimulated by Ca2+/calmodulin. Studies have shown that mice depleted of AC1 have attenuated inflammatory pain response, while AC1 /AC8 double-knockout mice display both attenuated pain response and opioid dependence. Thus, AC1 has emerged as a promising new target for treating chronic pain and opioid abuse. We discovered that the 1,3,4-oxadiazole scaffold inhibits Ca2+/calmodulin-stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in cells stably expressing either AC1 or AC8. We then carried out structure-activity relationship studies, in which we designed and synthesized 65 analogs, to modulate potency and selectivity versus each AC isoform in cells. Furthermore, molecular docking of the analogs into an AC1 homology model suggests the molecules may bind at the ATP binding site. Finally, a prioritized analog was tested in a mouse model of inflammatory pain and exhibited modest analgesic properties. In summary, our data indicate the 1,3,4-oxadiazoles represent a novel scaffold for the cellular inhibition of Ca2+/calmodulin-stimulated AC1- and AC8 CAMP and warrant further exploration as potential lead compounds for the treatment of chronic inflammatory pain. (C) 2018 Elsevier Masson SAS. All rights reserved.