N-[2-(5-羟基-2-甲基-1H-吲哚-3-基)乙基]-2-甲氧基乙酰胺 | 1292285-54-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: N-[2-(5-羟基-2-甲基-1H-吲哚-3-基)乙基]-2-甲氧基乙酰胺
• 英文名称: SPRi3
• 英文别名: N-[2-(5-hydroxy-2-methyl-1H-indol-3-yl)ethyl]-2-methoxyacetamide
• CAS: 1292285-54-1
• 化学式: C₁₄H₁₈N₂O₃
• 分子量: 262.309
• InChiKey: YBXBWBBVLXZQBJ-UHFFFAOYSA-N

物化性质

• 沸点：
  561.9±50.0 °C(Predicted)
• 密度：
  1.241±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO：100 mM，乙醇：100 mM

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  74.4
• 氢给体数：
  3
• 氢受体数：
  3

制备方法与用途

生物活性

SPR inhibitor 3 (SPRi3) 是一种有效的 sepiapterin 还原酶 (SPR) 抑制剂。在非细胞体系中，SPR inhibitor 3 (SPRi3) 与人 SPR 的结合亲和力较高（IC50=74 nM），并在细胞检测中有效降低生物喋呤水平（IC50=5.2 μM）。研究发现，SPR inhibitor 3 (SPRi3) 能通过减少 BH4 水平来减轻神经性和炎症性疼痛。

靶点

• IC50: 74 nM (sepiapterin reductase)

体外研究

SPR inhibitor 3 (SPRi3) 还显著降低了小鼠原代感觉神经元中的 SPR 活性（IC50=0.45 μM），同时未影响 GTP 环化酶 1 (GCH1) 的活性。

反应信息

• 作为产物：
  描述：

  5-甲氧基-2-甲基吲哚 在 palladium 10% on activated carbon sodium tetrahydroborate 、 ammonium acetate 、 氢气 、 三溴化硼 、 potassium carbonate 、 三乙胺 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， -70.0~90.0 ℃ 、275.8 kPa 条件下， 反应 18.83h， 生成 N-[2-(5-羟基-2-甲基-1H-吲哚-3-基)乙基]-2-甲氧基乙酰胺
  参考文献：
  名称：

  [EN] SEPIAPTERIN REDUCTASE INHIBITORS FOR THE TREATMENT OF PAIN
  [FR] INHIBITEURS DE SÉPIAPTÉRINE RÉDUCTASE POUR LE TRAITEMENT DE LA DOULEUR

  摘要：

  本文介绍的是对丝氨酸脱氢酶（SPR）的小分子杂环抑制剂，以及它们的前药和药用盐。还包括这些化合物的药物组合物以及这些化合物用于治疗或预防疼痛（如炎症性疼痛、伤害性疼痛、功能性疼痛和神经病理性疼痛）的用途。

  公开号：

  WO2011047156A1

文献信息

• Pharmacological Assessment of Sepiapterin Reductase Inhibition on Tactile Response in the Rat
  作者：James T. Meyer、Brian A. Sparling、William J. McCarty、Maosheng Zhang、Marcus Soto、Stephen Schneider、Hao Chen、Jonathan Roberts、Helming Tan、Thomas Kornecook、Paul S. Andrews、Charles G. Knutson

  DOI：10.1124/jpet.119.257105

  日期：2019.11

  There is an unmet medical need for nonopioid pain therapies in human populations; several pathways are under investigation for possible therapeutic intervention. Tetrahydrobiopterin (BH4) has received attention recently as a mediator of neuropathic pain. Recent reports have implicated sepiapterin reductase (SPR) in this pain pathway as a regulator of BH4 production. To evaluate the role of SPR inhibition on BH4 reduction, we developed analytical methods to monitor the relationship between the plasma concentration of test article and endogenous pterins and applied these in the rat spinal nerve ligation pain model. Sepiapterin is an endogenous substrate, which accumulates upon inhibition of SPR. In response to a potent inhibitor of SPR, plasma concentrations of sepiapterin increased proportionally with exposure. An indirect-effect pharmacokinetic/pharmacodynamic model was developed to describe the relationship between the plasma pharmacokinetics of test article and plasma sepiapterin levels in the rat, which was used to determine an in vivo SPR IC50 value. SPR inhibition and mechanical allodynia were assessed coordinately with pterin biomarkers in plasma and at the site of neuronal injury (i.e., dorsal root ganglion). Upon daily oral administration for 3 consecutive days, unbound plasma concentrations of test article exceeded the unbound in vivo rat SPR IC90 throughout the dose intervals, leading to a 60% reduction in BH4 in the dorsal root ganglion. Despite evidence for pharmacological modulation of the BH4 pathway, there was no significant effect on the tactile paw withdrawal threshold relative to vehicle-treated controls.

  在人类中，对于非阿片类镇痛药物存在未被满足的医疗需求；目前正研究多条可能用于治疗干预的通路。四氢生物蝶呤（BH4）最近作为一种神经病理性疼痛介质引起了关注。最近的研究报告将塞帕肽还原酶（SPR）与这一疼痛通路联系起来，将其视为调节BH4生成的一种酶。为了评价SPR抑制对BH4减少的作用，我们开发了分析方法来监测试验药物血浆浓度与内源性蝶呤之间的关系，并将其应用于大鼠脊神经结扎疼痛模型中。塞帕蝶呤是一种内源性底物，在SPR被抑制的情况下会累积。在高强度SPR抑制剂的作用下，塞帕蝶呤的血浆浓度与暴露量成比例地增加。我们构建了一个间接效应药代动力学/药效学模型，以描述试验药物血浆药代动力学与大鼠血浆中塞帕蝶呤水平之间的关系，并据此计算体内SPR的IC50值。我们在血浆及神经元损伤部位（即背根神经节）协同评估了SPR抑制、机械异常痛觉及蝶呤生物标志物。连续3天每日口服给药后，试验药物的未结合血浆浓度在整个剂量间隔期内均超过了大鼠体内未结合的SPR的IC90值，从而使背根神经节中的BH4含量减少了60%。尽管有证据表明BH4通路被药理学调控，但与对照组相比，试验组在触觉性爪回缩阈值方面并未表现出显著影响。
• Methods and assays relating to sepiapterin reductase inhibition
  申请人：CHILDREN'S MEDICAL CENTER CORPORATION

  公开号：US10365267B2

  公开（公告）日：2019-07-30

  Described herein are methods and assays relating to the inhibition of sepiapterin reductase and measuring said inhibition by measuring the level of sepiapterin. In some embodiments, the methods can further relate to treating a subject with BH4 and/or BH2.

  本文描述的是与抑制sepiapterin还原酶和通过测量sepiapterin水平来测量所述抑制作用有关的方法和检测方法。在某些实施方案中，这些方法可进一步涉及用 BH4 和/或 BH2 治疗受试者。
• Sepiapterin Reductase Inhibitors For The Treatment of Pain
  申请人：Blagg Julian

  公开号：US20120322800A1

  公开（公告）日：2012-12-20

  Disclosed herein are small molecule heterocyclic inhibitors of sepiapterin reductase (SPR), and prodrugs and pharmaceutically acceptable salts thereof. The Also featured are pharmaceutical compositions of the compounds and uses of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, and neuropathic pain).
• SEPIAPTERIN REDUCTASE INHIBITORS FOR THE TREATMENT OF PAIN
  申请人：Children's Medical Center Corporation

  公开号：US20160031812A1

  公开（公告）日：2016-02-04

  Disclosed herein are small molecule heterocyclic inhibitors of sepiapterin reductase (SPR), and prodrugs and pharmaceutically acceptable salts thereof. The Also featured are pharmaceutical compositions of the compounds and uses of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, and neuropathic pain).
• METHODS AND ASSAYS RELATING TO SEPIAPTERIN REDUCTASE INHIBITION
  申请人：CHILDREN'S MEDICAL CENTER CORPORATION

  公开号：US20170307591A1

  公开（公告）日：2017-10-26

  Described herein are methods and assays relating to the inhibition of sepiapterin reductase and measuring said inhibition by measuring the level of sepiapterin. In some embodiments, the methods can further relate to treating a subject with BH4 and/or BH2.