凯拉托芬 | 92175-57-0

• 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
• 中文名称: 凯拉托芬
• 英文名称: Kelatorphan
• 英文别名: (2S)-2-[[(2R)-2-benzyl-4-(hydroxyamino)-4-oxobutanoyl]amino]propanoic acid
• CAS: 92175-57-0
• 化学式: C₁₄H₁₈N₂O₅
• 分子量: 294.307
• InChiKey: OJCFZTVYDSKXNM-GXSJLCMTSA-N

物化性质

• 密度：
  1.301±0.06 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  21
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  116
• 氢给体数：
  4
• 氢受体数：
  5

制备方法与用途

生物活性

Kelatorphan 是脑啡肽降解酶的全抑制剂。

靶点

Enkephalin degrading enzyme.

体内研究

单独给予 Kelatorphan（50 μg），可显著增加完整的 ([^{3}H]) 脑啡肽含量，相当于总回收放射活性的 80±11%。在正常清醒大鼠中，Kelatorphan （10±20 mg/kg i.v.）能增加每分钟通气量。这种增加主要是由于呼吸频率呈剂量依赖性增加引起的。在关节炎大鼠中，Kelatorphan（20 mg/kg i.v.）也能增加通气量，并且与非关节炎大鼠之间没有显著差异。在戊巴比妥麻醉的大鼠中，Kelatorphan（20 mg/kg, n=6）于给药后 10±15 分钟也能产生轻微但显著的呼吸增加（116%）。Kelatorphan 的作用不会被小剂量纳洛酮（0.2 mg/kg i.v., 15 min 前）所拮抗，但在清醒大鼠中，较大剂量的纳洛酮（1 mg/kg）在给药后的 5 和 10 分钟内显著拮抗了 Kelatorphan 的作用。

反应信息

• 作为产物：
  描述：

  (R)-2-苄基丁二酸 4-叔丁酯 在 palladium on activated charcoal N-甲基吗啉 、 氢气 、 1-羟基苯并三唑 、 1-羟基苯并三唑一水物 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 氯仿 为溶剂， 25.0 ℃ 、34.48 kPa 条件下， 反应 33.2h， 生成 凯拉托芬
  参考文献：
  名称：

  强效脑啡肽酶抑制剂 Kelatorphan 的简明不对称合成

  摘要：

  摘要 从市售的氢化肉桂酰氯分七个步骤完成了脑啡肽酶抑制剂 Kelatorphan 的简明不对称合成。该合成的关键步骤是利用 Oppolzer 冰片烷-舒坦烷基化方法形成不对称 CC 键。

  DOI：

  10.1080/00397919208020851

文献信息

• Neutral metalloendopeptidase inhibitors in the treatment of hypertension
  申请人：SCHERING CORPORATION

  公开号：EP0254032A2

  公开（公告）日：1988-01-27

  The method of treating hypertension with neutral metalloendopeptidase (NMEP) inhibitors, NMEP inhibitors in combination with atrial peptides, and NMEP inhibitors in combination with angiotensin converting enzyme inhibitors, as well as pharmaceutical compositions therefor, are disclosed.

  本研究公开了使用中性金属内肽酶（NMEP）抑制剂、NMEP 抑制剂与心房肽联合使用、NMEP 抑制剂与血管紧张素转换酶抑制剂联合使用治疗高血压的方法及其药物组合物。
• New bidentates as full inhibitors of enkephalin-degrading enzymes: synthesis and analgesic properties
  作者：Marie Claude Fournie-Zaluski、Annie Coulaud、Romaine Bouboutou、Pierre Chaillet、Jocelyne Devin、Gilles Waksman、Jean Costentin、Bernard P. Roques

  DOI：10.1021/jm00147a007

  日期：1985.9

  New compounds were designed to fully inhibit the in vitro metabolism of enkephalins, ensured by three different metallopeptidases. For this purpose, bidentate ligands as hydroxamate and N-hydroxy-N-formylamino groups were selected as highly potent metal coordinating agents and introduced on Phe-Gly and Phe-Ala related structures. Compounds corresponding to the general formula HC(O)N(OH)CH2CH(CH2Ph)CONHCH2COOH (compound 7) and HN(OH)C(O)CH2CH(CH2Ph)CONHCH(R)COOH (compound 11, R = H; compound 13, R = CH3) behave as full inhibitors of the three enzymes, with IC50's in the nanomolar range for enkephalinase, from 0.3 microM to 1 nM for dipeptidylaminopeptidase, and in the micromolar range for a biologically relevant aminopeptidase. Two diastereoisomers of the most active inhibitor 13 were separated by HPLC and their stereochemistry was assigned by 1H NMR spectroscopy. Both isomers were efficient as enkephalinase blockers, but only the RS isomer, designated kelatorphan, was able to strongly inhibit aminopeptidase and dipeptidylaminopeptidase. Intracerebroventricular injection in mice of these mixed inhibitors, especially kelatorphan, led to naloxone reversible analgesic responses (hot-plate test) that were slightly better than those produced by a mixture of thiorphan and bestatin, two potent inhibitors of enkephalinase and aminopeptidase, respectively. Kelatorphan was also more efficient in potentiating the analgesia induced by a subanalgesic dose of Met-enkephalin. All these results support a physiological role in pain transmission for enkephalinase and a probably synaptic aminopeptidase M.
• IDENTIFICATION AND TARGETED MODULATION OF GENE SIGNALING NETWORKS
  申请人：CAMP4 THERAPEUTICS CORPORATION

  公开号：US20210254056A1

  公开（公告）日：2021-08-19

  The present invention provides methods and compositions for the evaluation, alteration and/or optimization of gene signaling. Methods and systems are also provided which exploit the information generated in the identification of new targets and non-canonical signaling pathways.
• US4740499A
  申请人：——

  公开号：US4740499A

  公开（公告）日：1988-04-26
• US4749688A
  申请人：——

  公开号：US4749688A

  公开（公告）日：1988-06-07