cis-4-<4-(2H-tetrazol-5-yl)but-1-yl>piperidine-2-carboxylic acid | 129920-17-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: cis-4-<4-(2H-tetrazol-5-yl)but-1-yl>piperidine-2-carboxylic acid
• 英文别名: cis-4-[4-(2H-tetrazol-5-yl)but-1-yl]piperidine-2-carboxylic acid；(2S,4R)-4-[4-(2H-tetrazol-5-yl)butyl]piperidine-2-carboxylic acid
• CAS: 129920-17-8
• 化学式: C₁₁H₁₉N₅O₂
• 分子量: 253.304
• InChiKey: FXPPVZICKBRICG-BDAKNGLRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  18
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  104
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-(2-cyanopyrid-4-yl)prop-1-yl acetate 在 Rh/Al₂O₃ 盐酸 、 sodium hydroxide 、 4 A molecular sieve 、 氢气 、 sodium hydride 、 N,N-二异丙基乙胺 、 pyridinium chlorochromate 、 三正丁基叠氮化锡 作用下， 以 二氯甲烷 为溶剂， 反应 8.5h， 生成 cis-4-<4-(2H-tetrazol-5-yl)but-1-yl>piperidine-2-carboxylic acid
  参考文献：
  名称：

  4-(Tetrazolylalkyl)piperidine-2-carboxylic acids. Potent and selective N-methyl-D-aspartic acid receptor antagonists with a short duration of action

  摘要：

  We have prepared a series of cis-4-(tetrazolylalkyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS-19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [H-3]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4-mu-M. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.

  DOI：

  10.1021/jm00105a016

文献信息

• 4-(Tetrazolylalkyl)piperidine-2-carboxylic acids. Potent and selective N-methyl-D-aspartic acid receptor antagonists with a short duration of action
  作者：Paul L. Ornstein、Darryle D. Schoepp、M. Brian Arnold、J. David Leander、David Lodge、Jonathan W. Paschal、Tom Elzey

  DOI：10.1021/jm00105a016

  日期：1991.1

  We have prepared a series of cis-4-(tetrazolylalkyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS-19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [H-3]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4-mu-M. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.