Boc-Tyr(t-Bu)-D-Ala-Gly-Phe-Pro-Leu-Trp(Boc)-OH | 1006724-58-8

• 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: Boc-Tyr(t-Bu)-D-Ala-Gly-Phe-Pro-Leu-Trp(Boc)-OH
• 英文别名: Boc-Tyr(tBu)-D-Ala-Gly-Phe-Pro-Leu-Trp(Boc)-OH；(2S)-2-[[(2S)-4-methyl-2-[[(2S)-1-[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-[4-[(2-methylpropan-2-yl)oxy]phenyl]propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]amino]-3-[1-[(2-methylpropan-2-yl)oxycarbonyl]indol-3-yl]propanoic acid
• CAS: 1006724-58-8
• 化学式: C₅₉H₈₀N₈O₁₃
• 分子量: 1109.33
• InChiKey: KJHKQOMRDHFTFO-WAKRJQMUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.7
• 重原子数：
  80
• 可旋转键数：
  27
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.51
• 拓扑面积：
  282
• 氢给体数：
  7
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  Boc-Tyr(t-Bu)-D-Ala-Gly-Phe-Pro-Leu-Trp(Boc)-OH 、 3,5-双三氟甲基苯基-N-甲基甲胺 在 苯酚 caesium carbonate 、 茴香硫醚 、 乙二醇 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 生成 H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NMe-3,5-Bzl(CF3)2
  参考文献：
  名称：

  A Structure–Activity Relationship Study and Combinatorial Synthetic Approach of C-Terminal Modified Bifunctional Peptides That Are δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

  摘要：

  A series of bifunctional peptides with opioid agonist and substance P antagonist bioactivities were designed with the concept of overlapping pharmacophores. In this concept, the bifunctional peptides were expected to interact with each receptor separately in the spinal dorsal horn where both the opioid receptors and the NK1 receptors were found to be expressed, to show an enhanced analgesic effect, no opioid-induced tolerance, and to provide better compliance than coadministration of two drugs. Compounds were synthesized using a two-step combinatorial method for C-terminal modification. In the method, the protected C-terminal-free carboxyl peptide, Boc-Tyr(tBu)-D-Ala-Gly Phe-Pro-Leu-Trp(Boc)-OH, was synthesized as a shared intermediate using Fmoc solid phase chemistry on a 2-chlorotrityl resin. This intermediate was esterified or amidated in solution phase. The structure-activity relationships (SAR) showed that the C-terminus acted as not only a critical pharmacophore for the substance P antagonist activities, but as an address region for the opioid agonist pharmacophore that is structurally distant from the C-terminal. Among the peptides, H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl (3) demonstrated high binding affinities at both delta and mu receptors (K-i = 10 and 0.65 nM, respectively) with efficient agonist functional activity in the mouse isolated vas deferens (MVD) and guinea pig isolated ileum (GPI) assays (IC50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation (K, = 26 nM) and good affinity for the hNK1 receptor (K-i = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.

  DOI：

  10.1021/jm070332f
• 作为产物：
  描述：

  L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester hydrochloride 在 2-chlorotrityl resin 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 Boc-Tyr(t-Bu)-D-Ala-Gly-Phe-Pro-Leu-Trp(Boc)-OH
  参考文献：
  名称：

  BIFUNCTIONAL ANALGESIC COMPOUNDS FOR OPIOID RECEPTOR AGONISTS AND NEUROKININ-1 RECEPTOR ANTAGONISTS

  摘要：

  本发明提供了一种新型嵌合化合物，其包括在其N-末端具有激动剂阿片受体结合基团和在其C-末端具有拮抗剂神经激肽-1（NK1）受体结合基团，用于产生镇痛作用，以及包括该嵌合化合物的药物组合物、制备该化合物的方法，以及使用该新型嵌合化合物治疗疼痛的方法。

  公开号：

  US20080039404A1

文献信息

• BIFUNCTIONAL ANALGESIC COMPOUNDS FOR OPIOID RECEPTOR AGONISTS AND NEUROKININ-1 RECEPTOR ANTAGONISTS
  申请人：Hruby Victor

  公开号：US20080039404A1

  公开（公告）日：2008-02-14

  The present invention provides a novel chimeric compound comprising an agonist opioid receptor binding moiety at its N-terminus and an antagonist neurokinin-1 (NK1) receptor binding moiety at its C-terminus for producing analgesia, a pharmaceutical composition comprising the chimeric compound, a method of making the compound, and a method of treating pain using the novel chimeric compounds.

  本发明提供了一种新型嵌合化合物，其包括在其N-末端具有激动剂阿片受体结合基团和在其C-末端具有拮抗剂神经激肽-1（NK1）受体结合基团，用于产生镇痛作用，以及包括该嵌合化合物的药物组合物、制备该化合物的方法，以及使用该新型嵌合化合物治疗疼痛的方法。
• A Structure–Activity Relationship Study and Combinatorial Synthetic Approach of C-Terminal Modified Bifunctional Peptides That Are δ/μ Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists
  作者：Takashi Yamamoto、Padma Nair、Josef Vagner、Tally Largent-Milnes、Peg Davis、Shou-wu Ma、Edita Navratilova、Sharif Moye、Suneeta Tumati、Josephine Lai、Henry I. Yamamura、Todd W. Vanderah、Frank Porreca、Victor J. Hruby

  DOI：10.1021/jm070332f

  日期：2008.3.13

  A series of bifunctional peptides with opioid agonist and substance P antagonist bioactivities were designed with the concept of overlapping pharmacophores. In this concept, the bifunctional peptides were expected to interact with each receptor separately in the spinal dorsal horn where both the opioid receptors and the NK1 receptors were found to be expressed, to show an enhanced analgesic effect, no opioid-induced tolerance, and to provide better compliance than coadministration of two drugs. Compounds were synthesized using a two-step combinatorial method for C-terminal modification. In the method, the protected C-terminal-free carboxyl peptide, Boc-Tyr(tBu)-D-Ala-Gly Phe-Pro-Leu-Trp(Boc)-OH, was synthesized as a shared intermediate using Fmoc solid phase chemistry on a 2-chlorotrityl resin. This intermediate was esterified or amidated in solution phase. The structure-activity relationships (SAR) showed that the C-terminus acted as not only a critical pharmacophore for the substance P antagonist activities, but as an address region for the opioid agonist pharmacophore that is structurally distant from the C-terminal. Among the peptides, H-Tyr-D-Ala-Gly-Phe-Pro-Leu-Trp-NH-Bzl (3) demonstrated high binding affinities at both delta and mu receptors (K-i = 10 and 0.65 nM, respectively) with efficient agonist functional activity in the mouse isolated vas deferens (MVD) and guinea pig isolated ileum (GPI) assays (IC50 = 50 and 13 nM, respectively). Compound 3 also showed a good antagonist activity in the GPI assay with substance P stimulation (K, = 26 nM) and good affinity for the hNK1 receptor (K-i = 14 nM). Consequently, compound 3 is expected to be a promising and novel type of analgesic with bifunctional activities.