(3S)-5-methyl-3-(((1-(4-(nitrooxy)butanoyloxy)ethoxy)carbonylamino)methyl)hexanoic acid | 1331782-63-8

• 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: (3S)-5-methyl-3-(((1-(4-(nitrooxy)butanoyloxy)ethoxy)carbonylamino)methyl)hexanoic acid
• 英文别名: (3S)-5-methyl-3-[[1-(4-nitrooxybutanoyloxy)ethoxycarbonylamino]methyl]hexanoic acid
• CAS: 1331782-63-8
• 化学式: C₁₅H₂₆N₂O₉
• 分子量: 378.379
• InChiKey: RLPWJINJFNMXBM-KIYNQFGBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  26
• 可旋转键数：
  14
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  157
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-{[(4-nitrophenoxy)carbonyl]oxy}ethyl 4-(nitrooxy)butanoate 、 普瑞巴林 在 三甲基氯硅烷 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 (3S)-5-methyl-3-(((1-(4-(nitrooxy)butanoyloxy)ethoxy)carbonylamino)methyl)hexanoic acid
  参考文献：
  名称：

  Repeated Dosing with NCX1404, a Nitric Oxide-Donating Pregabalin, Re-establishes Normal Nociceptive Responses in Mice with Streptozotocin-Induced Painful Diabetic Neuropathy

  摘要：

  NCX1404 [(3S)-5-甲基-3-(((1-(4-硝酸氧丁酰氧基)乙氧基)碳酰氨基)甲基)己酸]是一种新型的释放一氧化氮(NO)的普瑞巴林，它易于在体内吸收和代谢为普瑞巴林和NO。我们在链脲佐菌素(STZ)诱导的痛性糖尿病周围神经病变(PDN)小鼠中，通过急性给药或连续7天、14天和21天每日重复口服给药，确定了NCX1404的抗痛觉过敏反应。以普瑞巴林及其与NO供体单硝酸异山梨酯(ISMN)组合作为对照组进行比较。在平行实验中使用液相色谱串联质谱(LC-MS/MS)监测NCX1404或普瑞巴林给药后普瑞巴林和亚硝酸盐的血药浓度，后者作为NO释放的替代标记物。NCX1404和普瑞巴林在急性给药后对STZ小鼠的抗痛觉过敏作用中表现出相似的普瑞巴林水平。然而，每日给药21天后，NCX1404显示出疾病修饰特性，表现为依时间、剂量依赖性地逆转STZ诱导的机械痛觉过敏（足底撤回阈值(PWT)Veh_21d = 1.3 ± 0.15 g为对照组；PWTNCX1404_21d = 1.4 ± 0.5 g, 2.9 ± 0.2 g*和4.1 ± 0.2 g*分别为19、63和190 μ mol/kg口服灌胃(PO)的NCX1404；* P < 0.05与对照组相比）。普瑞巴林在等摩尔剂量(190 μ mol/kg, PO)时并没有显示出这种效果（PWTPregab_21d = 1.4 ± 0.1 g*, * P < 0.05与等摩尔NCX1404相比）。此外，NO供体ISMN（52.3 μ mol/kg, PO）单独或与普瑞巴林(63 μ mol/kg）联合均在7天时有效（PWTVeh_7d = 1.7 ± 0.16 g; PWTISMN_7d = 3.9 ± 0.34 g*; PWTPregab_7d = 1.3 ± 0.07 g; PWTISMN+pregab_7d = 3.8 ± 0.29 g*; * P < 0.05）但在后期时间点上无效。NCX1404的长期效应独立于残留药物暴露，并且在治疗停止后持续数天。总之，与普瑞巴林一样，NCX1404是一种有效的抗痛觉过敏制剂。与普瑞巴林不同，重复给药的NCX1404恢复了STZ诱导的PDN小鼠正常伤害感受反应。

  DOI：

  10.1124/jpet.115.230193

文献信息

• [EN] NITRIC OXIDE RELEASING COMPOUNDS FOR THE TREATMENT OF NEUROPATHIC PAIN<br/>[FR] COMPOSÉS LIBÉRANT DU MONOXYDE D'AZOTE POUR LE TRAITEMENT DE LA DOULEUR NEUROPATHIQUE
  申请人：NICOX SA

  公开号：WO2011101245A1

  公开（公告）日：2011-08-25

  The invention relates to nitrooxyderivatives of Gamma- aminobutyric acid analogs (GABA analogs) for treating neuropathic pain and in particular diabetic neuropathy. The invention also relates to pharmaceutical formulation comprising such derivatives, to a process for their preparation.

  该发明涉及γ-氨基丁酸类似物（GABA类似物）的硝基氧衍生物，用于治疗神经病性疼痛，特别是糖尿病性神经病变。该发明还涉及包含这些衍生物的药物配方，以及它们的制备方法。
• Repeated Dosing with NCX1404, a Nitric Oxide-Donating Pregabalin, Re-establishes Normal Nociceptive Responses in Mice with Streptozotocin-Induced Painful Diabetic Neuropathy
  作者：K. Varani、F. Vincenzi、M. Targa、A. Ravani、E. Bastia、L. Storoni、S. Brambilla、N. Almirante、F. Impagnatiello

  DOI：10.1124/jpet.115.230193

  日期：2016.4.1

  NCX1404 [(3 S )-5-methyl-3-(((1-(4-(nitrooxy)butanoyloxy)ethoxy)carbonylamino) methyl)hexanoic acid] is a novel nitric oxide (NO)–donating pregabalin that is readily absorbed and processed in vivo to pregabalin and NO. We determined the antiallodynic response of NCX1404 after acute or after 7, 14, and 21 days of repeated daily oral dosing in mice with streptozotocin (STZ)-induced painful diabetic neuropathy (PDN). Pregabalin and its combination with the NO donor isosorbide mononitrate (ISMN) were used for comparison. The blood levels of pregabalin and nitrites, used as surrogate marker of NO release, after NCX1404 or pregabalin dosing were monitored in parallel experiments using liquid chromatography with tandem mass spectrometry (LC-MS/MS). NCX1404 and pregabalin resulted in similar pregabalin levels as it was their antiallodynic activity after acute dosing in STZ mice. However, NCX1404 resulted in disease-modifying properties when administered daily for 21 days, as indicated by the time- and dose-dependent reversal of STZ-induced mechanical allodynia (paw withdrawal threshold [PWT]Veh_21d = 1.3 ± 0.15 g for vehicle; PWTNCX1404_21d = 1.4 ± 0.5 g, 2.9 ± 0.2 g* and 4.1 ± 0.2 g*, respectively for 19, 63, and 190 μ mol/kg, oral gavage [PO] of NCX1404; * P < 0.05 versus vehicle). This effect was not shared by pregabalin at equimolar doses (190 μ mol/kg, PO, PWTPregab_21d = 1.4 ± 0.1 g*, * P < 0.05 versus equimolar NCX1404). In addition, the NO donor ISMN (52.3 μ mol/kg, PO) alone or combined with pregabalin (63 μ mol/kg) was active at 7 days (PWTVeh_7d = 1.7 ± 0.16 g; PWTISMN_7d = 3.9 ± 0.34 g*; PWTPregab_7d = 1.3 ± 0.07 g; PWTISMN+pregab_7d = 3.8 ± 0.29 g*; * P < 0.05) but not at later time points. The long-term effect of NCX1404 was independent of residual drug exposure and lasted for several days after the treatment was stopped. In summary, like pregabalin, NCX1404 is an effective antiallodynic agent. Differently from pregabalin, repeated dosing of NCX1404 re-established normal nociceptive responses in STZ-induced PDN in mice.

  NCX1404 [(3S)-5-甲基-3-(((1-(4-硝酸氧丁酰氧基)乙氧基)碳酰氨基)甲基)己酸]是一种新型的释放一氧化氮(NO)的普瑞巴林，它易于在体内吸收和代谢为普瑞巴林和NO。我们在链脲佐菌素(STZ)诱导的痛性糖尿病周围神经病变(PDN)小鼠中，通过急性给药或连续7天、14天和21天每日重复口服给药，确定了NCX1404的抗痛觉过敏反应。以普瑞巴林及其与NO供体单硝酸异山梨酯(ISMN)组合作为对照组进行比较。在平行实验中使用液相色谱串联质谱(LC-MS/MS)监测NCX1404或普瑞巴林给药后普瑞巴林和亚硝酸盐的血药浓度，后者作为NO释放的替代标记物。NCX1404和普瑞巴林在急性给药后对STZ小鼠的抗痛觉过敏作用中表现出相似的普瑞巴林水平。然而，每日给药21天后，NCX1404显示出疾病修饰特性，表现为依时间、剂量依赖性地逆转STZ诱导的机械痛觉过敏（足底撤回阈值(PWT)Veh_21d = 1.3 ± 0.15 g为对照组；PWTNCX1404_21d = 1.4 ± 0.5 g, 2.9 ± 0.2 g*和4.1 ± 0.2 g*分别为19、63和190 μ mol/kg口服灌胃(PO)的NCX1404；* P < 0.05与对照组相比）。普瑞巴林在等摩尔剂量(190 μ mol/kg, PO)时并没有显示出这种效果（PWTPregab_21d = 1.4 ± 0.1 g*, * P < 0.05与等摩尔NCX1404相比）。此外，NO供体ISMN（52.3 μ mol/kg, PO）单独或与普瑞巴林(63 μ mol/kg）联合均在7天时有效（PWTVeh_7d = 1.7 ± 0.16 g; PWTISMN_7d = 3.9 ± 0.34 g*; PWTPregab_7d = 1.3 ± 0.07 g; PWTISMN+pregab_7d = 3.8 ± 0.29 g*; * P < 0.05）但在后期时间点上无效。NCX1404的长期效应独立于残留药物暴露，并且在治疗停止后持续数天。总之，与普瑞巴林一样，NCX1404是一种有效的抗痛觉过敏制剂。与普瑞巴林不同，重复给药的NCX1404恢复了STZ诱导的PDN小鼠正常伤害感受反应。