[(S)-1-[4-(5-{4-[(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-butyl}-3-methyl-6-oxo-1,6-dihydro-pyrazin-2-yl)-butylcarbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester | 234450-13-6

• 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: [(S)-1-[4-(5-{4-[(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-butyl}-3-methyl-6-oxo-1,6-dihydro-pyrazin-2-yl)-butylcarbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester
• 英文别名: tert-butyl N-[(2S)-3-(4-hydroxyphenyl)-1-[4-[5-[4-[[(2S)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoyl]amino]butyl]-3-methyl-6-oxo-1H-pyrazin-2-yl]butylamino]-1-oxopropan-2-yl]carbamate
• CAS: 234450-13-6
• 化学式: C₄₁H₅₈N₆O₉
• 分子量: 778.946
• InChiKey: WLHYVMPOQXKYOR-HEVIKAOCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  56
• 可旋转键数：
  22
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  217
• 氢给体数：
  7
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  [(S)-1-[4-(5-{4-[(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-butyl}-3-methyl-6-oxo-1,6-dihydro-pyrazin-2-yl)-butylcarbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester 在 苯甲醚 、 三氟乙酸 作用下， 生成 (S)-2-Amino-N-[4-(5-{4-[(S)-2-amino-3-(4-hydroxy-phenyl)-propionylamino]-butyl}-3-methyl-6-oxo-1,6-dihydro-pyrazin-2-yl)-butyl]-3-(4-hydroxy-phenyl)-propionamide
  参考文献：
  名称：

  Synthesis of Pyrazinone Ring-Containing Opioid Mimetics and Examination of Their Opioid Receptor-Binding Activity.

  摘要：

  二肽氯甲基酮环化后得到 6-(4-氨基丁基)-3-羧乙基-5-甲基-2(1H)-吡嗪酮、3-(4-氨基丁基)-6-羧乙基-5-甲基-2(1H)-吡嗪酮和 3,6-双(4-氨基丁基)-5-甲基-2(1H)-吡嗪酮，将它们插入脑啡肽序列可得到阿片类仿效物。由此证实，吡嗪酮环可以很容易地插入肽序列中，以评估具有生物活性的肽所需的结构成分。

  DOI：

  10.1248/cpb.47.1193
• 作为产物：
  描述：

  benzyl N-[4-[3-methyl-6-oxo-5-[4-(phenylmethoxycarbonylamino)butyl]-1H-pyrazin-2-yl]butyl]carbamate 在 钯 氢气 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 溶剂黄146 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 [(S)-1-[4-(5-{4-[(S)-2-tert-Butoxycarbonylamino-3-(4-hydroxy-phenyl)-propionylamino]-butyl}-3-methyl-6-oxo-1,6-dihydro-pyrazin-2-yl)-butylcarbamoyl]-2-(4-hydroxy-phenyl)-ethyl]-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH₂)_n]-2(1H)-pyrazinone with Central-Mediated Analgesia

  摘要：

  The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.

  DOI：

  10.1021/jm0304616

文献信息

• Synthesis of Pyrazinone Ring-Containing Opioid Mimetics and Examination of Their Opioid Receptor-Binding Activity.
  作者：Yoshio OKADA、Atsuko FUKUMIZU、Motohiro TAKAHASHI、Toshio YOKOI、Yuko TSUDA、Sharon D. BRYANT、Lawrence H. LAZARUS

  DOI：10.1248/cpb.47.1193

  日期：——

  Cyclization of dipeptidyl chloromethyl ketones gave 6-(4-aminobutyl)-3-carboxyethyl-5-methyl-2(1H)-pyrazinone, 3-(4-aminobutyl)-6-carboxyethyl-5-methyl-2(1H)-pyrazinone, and 3, 6-bis(4-aminobutyl)-5-methyl-2(1H)-pyrazinone, which were inserted into the enkephalin sequence to give opioid mimetics. Thus, it was confirmed that a pyrazinone ring can be easily inserted into a peptide sequence in order to evaluate structural components required for biologically active peptides.

  二肽氯甲基酮环化后得到 6-(4-氨基丁基)-3-羧乙基-5-甲基-2(1H)-吡嗪酮、3-(4-氨基丁基)-6-羧乙基-5-甲基-2(1H)-吡嗪酮和 3,6-双(4-氨基丁基)-5-甲基-2(1H)-吡嗪酮，将它们插入脑啡肽序列可得到阿片类仿效物。由此证实，吡嗪酮环可以很容易地插入肽序列中，以评估具有生物活性的肽所需的结构成分。
• Oral Bioavailability of a New Class of μ-Opioid Receptor Agonists Containing 3,6-Bis[Dmt-NH(CH₂)<i>_n</i>]-2(1<i>H</i>)-pyrazinone with Central-Mediated Analgesia
  作者：Yunden Jinsmaa、Anna Miyazaki、Yoshio Fujita、Tingyou Li、Yutaka Fujisawa、Kimitaka Shiotani、Yuko Tsuda、Toshio Yokoi、Akihiro Ambo、Yusuke Sasaki、Sharon D. Bryant、Lawrence H. Lazarus、Yoshio Okada

  DOI：10.1021/jm0304616

  日期：2004.5.1

  The inability of opioid peptides to be transported through epithelial membranes in the gastrointestinal tract and pass the blood-brain barrier limits their effectiveness for oral application in an antinociceptive treatment regime. To overcome this limitation, we enhanced the hydrophobicity while maintaining the aqueous solubility properties in a class of opioidmimetic substances by inclusion of two identical N-termini consisting of Dmt (2',6'-dimethyl-L-tyrosine) coupled to a pyrazinone ring platform by means of alkyl chains to yield the class of 3,6-bis[Dmt-NH-(CH2)(n)],1-2(1H)-pyrazinones. These compounds displayed high mu-opioid receptor affinity (K(i)mu = 0.042-0.115 nM) and selectivity (K(i)delta/K(i)mu = 204-307) and functional p-opioid receptor agonism (guinea-pig ileum, IC50 = 1.3-1.9 nM) with little or undetectable bioactivity toward delta-opioid receptors (mouse vas deferens) and produced analgesia in mice in a naloxone reversible manner when administered centrally (intracerebroventricular, icv) or systemically (subcutaneously and orally). Furthermore, the most potent compound, 3,6-bis(3'-Dmt-aminopropyl)-5-methyl-2(1H)-pyrazinone (7') lacked functional delta-opioid receptor bioactivity and was 50-63-fold and 18-21-fold more active than morphine by icv administration as measured analgesia using tail-flick (spinal involvement) and hot-plate (supraspinal effect) tests, respectively; the compound ranged from 16 to 63% as potent upon systemic injection. These analgesic effects are many times greater than unmodified opioid peptides. The data open new possibilities for the rational design of potential opioid-mimetic drugs that pass through the epithelium of the gastrointestinal tract and the blood-brain barrier to target brain receptors.