2-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-7-azaspiro[3.5]nonane | 1225276-68-5

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-7-azaspiro[3.5]nonane
• 英文别名: 2-[3-[5-(Trifluoromethyl)pyridin-2-yl]oxyphenyl]-7-azaspiro[3.5]nonane
• CAS: 1225276-68-5
• 化学式: C₂₀H₂₁F₃N₂O
• 分子量: 362.395
• InChiKey: VVHVJCXBTVOMHC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  34.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  phenyl (3,4-dimethylisoxazol-5-yl)carbamate 、 2-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-7-azaspiro[3.5]nonane 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 生成 N-(3,4-dimethylisoxazol-5-yl)-2-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-7-azaspiro[3.5]nonane-7-carboxamide
  参考文献：
  名称：

  Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain

  摘要：

  Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.048
• 作为产物：
  描述：

  2-氯-5-三氟甲基吡啶 在 盐酸 、 caesium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-(3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-7-azaspiro[3.5]nonane
  参考文献：
  名称：

  Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain

  摘要：

  Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.08.048

文献信息

• Discovery of novel spirocyclic inhibitors of fatty acid amide hydrolase (FAAH). Part 2. Discovery of 7-azaspiro[3.5]nonane urea PF-04862853, an orally efficacious inhibitor of fatty acid amide hydrolase (FAAH) for pain
  作者：Marvin J. Meyers、Scott A. Long、Matthew J. Pelc、Jane L. Wang、Scott J. Bowen、Barbara A. Schweitzer、Mark V. Wilcox、Joseph McDonald、Sarah E. Smith、Susan Foltin、Jeanne Rumsey、Young-Sun Yang、Mark C. Walker、Satwik Kamtekar、David Beidler、Atli Thorarensen

  DOI：10.1016/j.bmcl.2011.08.048

  日期：2011.11

  Fatty acid amide hydrolase (FAAH) is an integral membrane serine hydrolase responsible for the degradation of fatty acid amide signaling molecules such as endocannabinoid anandamide (AEA), which has been shown to possess cannabinoid-like analgesic properties. Herein we report the optimization of spirocyclic 7-azaspiro[3.5]nonane and 1-oxa-8-azaspiro[4.5]decane urea covalent inhibitors of FAAH. Using an iterative design and optimization strategy, lead compounds were identified with a remarkable reduction in molecular weight and favorable CNS drug like properties. 3,4-Dimethylisoxazole and 1-methyltetrazole were identified as superior urea moieties for this inhibitor class. A dual purpose in vivo efficacy and pharmacokinetic screen was designed to be the key decision enabling experiment affording the ability to move quickly from compound synthesis to selection of preclinical candidates. On the basis of the remarkable potency, selectivity, pharmacokinetic properties and in vivo efficacy, PF-04862853 (15p) was advanced as a clinical candidate. (C) 2011 Elsevier Ltd. All rights reserved.