1-(4-((3,4-dichlorobenzyl)oxy)-3-fluorobenzyl)azetidine-3-carboxylic acid | 1240308-63-7

• 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: 1-(4-((3,4-dichlorobenzyl)oxy)-3-fluorobenzyl)azetidine-3-carboxylic acid
• 英文别名: 1-(4-(3,4-dichlorobenzyloxy)-3-fluorobenzyl)azetidine-3-carboxylic acid；1-[[4-[(3,4-Dichlorophenyl)methoxy]-3-fluorophenyl]methyl]azetidine-3-carboxylic acid
• CAS: 1240308-63-7
• 化学式: C₁₈H₁₆Cl₂FNO₃
• 分子量: 384.234
• InChiKey: DCJHQXHJMFDIMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3-氟-4-羟基苯腈 在 偶氮二甲酸二异丙酯 、 二异丁基氢化铝 、 溶剂黄146 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 、 甲苯 为溶剂， 反应 1.25h， 生成 1-(4-((3,4-dichlorobenzyl)oxy)-3-fluorobenzyl)azetidine-3-carboxylic acid
  参考文献：
  名称：

  Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P₅) Agonist for the Potential Treatment of Neurodegenerative Disorders

  摘要：

  S1P(5) is one of S receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood brain barrier, where it maintains barrier integrity in in vitro models (j Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P(5) modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., AAIC 2014). Herein we describe the development of a series of selective S1P(5) agonists that led to the identification of compound 29, which is highly selective for S1P(5) and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P(5) biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P(1). and S1P(3) function in rats. In addition, we found that 29 improves blood brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P(5) agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood brain barrier such as Alzheimer's disease or multiple sclerosis.

  DOI：

  10.1021/acs.jmedchem.5b00928

文献信息

• [EN] AGONISTS AND ANTAGONISTS OF THE S1P5 RECEPTOR, AND METHODS OF USES THEREOF<br/>[FR] AGONISTES ET ANTAGONISTES DU RÉCEPTEUR S1P5, ET LEURS PROCÉDÉS D'UTILISATION
  申请人：ABBOTT LAB

  公开号：WO2010093704A1

  公开（公告）日：2010-08-19

  Disclosed are compounds that are agonists or antagonists of the S1P5 receptor, compositions comprising said compounds, and methods of using said compounds and compositions. In certain embodiments, said compounds are 1-benzylazetidine-3-carboxylic acid derivatives. In certain embodiments, said methods relate to the treatment of neuropatic pain and/or a neurodegenerative disorder. In certain embodiments, said compounds may be used in combination with a second therapeutic agent.

  本文披露了作为S1P5受体激动剂或拮抗剂的化合物，包括含有这些化合物的组合物，以及使用这些化合物和组合物的方法。在某些实施例中，这些化合物是1-苄基氮杂环丙氨酸衍生物。在某些实施例中，这些方法涉及治疗神经痛和/或神经退行性疾病。在某些实施例中，这些化合物可以与第二治疗剂结合使用。
• Agonists and Antagonists of the S1P5 Receptor, and Methods of Use Thereof
  申请人：Harris Christopher M.

  公开号：US20100216762A1

  公开（公告）日：2010-08-26

  Disclosed are compounds that are agonists or antagonists of the S1P 5 receptor, compositions comprising said compounds, and methods of using said compounds and compositions. In certain embodiments, said compounds are 1-benzylazetidine-3-carboxylic acid derivatives. In certain embodiments, said methods relate to the treatment of neuropatic pain and/or a neurodegenerative disorder. In certain embodiments, said compounds may be used in combination with a second therapeutic agent.

  本发明涉及一种作为S1P5受体激动剂或拮抗剂的化合物，包括该化合物的组合物以及使用该化合物和组合物的方法。在某些实施例中，该化合物是1-苄基氮杂环丙氨酸衍生物。在某些实施例中，该方法涉及神经病性疼痛和/或神经退行性疾病的治疗。在某些实施例中，该化合物可以与第二种治疗药物联合使用。
• AGONISTS AND ANTAGONISTS OF THE SIP5 RECEPTOR, AND METHODS OF USES THEREOF
  申请人：Abbott Laboratories

  公开号：EP2395835A1

  公开（公告）日：2011-12-21
• Discovery of A-971432, An Orally Bioavailable Selective Sphingosine-1-Phosphate Receptor 5 (S1P₅) Agonist for the Potential Treatment of Neurodegenerative Disorders
  作者：Adrian D. Hobson、Christopher M. Harris、Elizabeth L. van der Kam、Sean C. Turner、Ayome Abibi、Ana L. Aguirre、Peter Bousquet、Tegest Kebede、Donald B. Konopacki、Gary Gintant、Youngjae Kim、Kelly Larson、John W. Maull、Nigel S. Moore、Dan Shi、Anurupa Shrestha、Xiubo Tang、Peng Zhang、Kathy K. Sarris

  DOI：10.1021/acs.jmedchem.5b00928

  日期：2015.12.10

  S1P(5) is one of S receptors for sphingosine-1-phosphate and is highly expressed on endothelial cells within the blood brain barrier, where it maintains barrier integrity in in vitro models (j Neuroinflamm. 2012, 9, 133). Little more is known about the effects of S1P(5) modulation due to the absence of tool molecules with suitable selectivity and drug-like properties. We recently reported that molecule A-971432 (Harris et al., 2010) (29 in this paper) is highly efficacious in reversing lipid accumulation and age-related cognitive decline in rats (Van der Kam, et al., AAIC 2014). Herein we describe the development of a series of selective S1P(5) agonists that led to the identification of compound 29, which is highly selective for S1P(5) and has excellent plasma and CNS exposure after oral dosing in preclinical species. To further support its suitability for in vivo studies of S1P(5) biology, we extensively characterized 29, including confirmation of its selectivity in pharmacodynamic assays of S1P(1). and S1P(3) function in rats. In addition, we found that 29 improves blood brain barrier integrity in an in vitro model and reverses age-related cognitive decline in mice. These results suggest that S1P(5) agonism is an innovative approach with potential benefit in neurodegenerative disorders involving lipid imbalance and/or compromised blood brain barrier such as Alzheimer's disease or multiple sclerosis.