(R)-2-(((tert-butoxycarbonyl)amino)(furan-2-yl)methyl)acrylic acid | 1384968-04-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 杂芳族化合物
• 英文名称: (R)-2-(((tert-butoxycarbonyl)amino)(furan-2-yl)methyl)acrylic acid
• 英文别名: Boc-(2-furyl)Map-OH
• CAS: 1384968-04-0
• 化学式: C₁₃H₁₇NO₅
• 分子量: 267.282
• InChiKey: RYRXDNAIOUKYSB-SNVBAGLBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.49
• 重原子数：
  19.0
• 可旋转键数：
  4.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  88.77
• 氢给体数：
  2.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (R)-2-(((tert-butoxycarbonyl)amino)(furan-2-yl)methyl)acrylic acid 在 碳酸氢钠 、 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.25h， 生成 (2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-5-(carbamoylamino)-N-[(2S)-1-[[(1R)-2-carbamoyl-1-(furan-2-yl)prop-2-enyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]pentanamide
  参考文献：
  名称：

  具有多位修饰的新型内啡肽类似物的设计，合成和生物学活性

  摘要：

  内吗啡肽（EM）-1和EM-2是最有效的内源性镇痛药，可以有效地将镇痛与不良反应的风险区分开。外围给药后代谢稳定性差和止痛效果不佳，不利于将EMs用作新型临床止痛剂。因此，在这里，我们旨在通过在[（2-furyl）Map4] EMs的位置2引入不同的双功能D-氨基酸来建立新的EM类似物。[（2-furyl）Map4] EMs与D-Arg 2或D-Cit 2的组合产生类似物，与μ阿片受体（MOR）的结合亲和力增强，并且对酶促降解的稳定性提高（t 1/2> 300分钟）。但是，这些类似物对MOR的激动活性略有降低。与吗啡类似，类似物[D-Cit 2，（2-furyl）Map4] EM-1（10）的外周给药显着抑制小鼠在多种疼痛模型中的疼痛行为。此外，这种EM-1类似物具有降低的耐受性，对胃肠道活动性的影响较小，并且没有明显的运动障碍。与天然EM相比，本文合成的EM类似物具有增强的代谢稳定性，生物利用度和镇痛特性。

  DOI：

  10.1016/j.bmc.2020.115438
• 作为产物：
  描述：

  tert-butyl (furan-2-yl(phenylsulfonyl)methyl)carbamate 在 1-[3,5-双（三氟甲基）苯基]-3-[（1S，2S）-2-（吡咯烷-1-基）环己基]硫脲 、 水 、 sodium methylate 、 potassium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 45.5h， 生成 (R)-2-(((tert-butoxycarbonyl)amino)(furan-2-yl)methyl)acrylic acid
  参考文献：
  名称：

  Design, Synthesis, and Pharmacological Characterization of Novel Endomorphin-1 Analogues as Extremely Potent μ-Opioid Agonists

  摘要：

  Recently we reported the synthesis and structure activity study of endomorphin-1 (EM-1) analogues containing novel, unnatural alpha-methylene-beta-aminopropanoic acids (Map). In the present study, we describe new EM-1 analogues containing Dmt(1), (R/S)-beta Pro(2), and (ph)Map(4)/(2-furyl)Map(4). All of the analogues showed a high affinity for the mu-opioid receptor (MOR) and increased stability in mouse brain homogenates. Of the new compounds, Dmt(1)-(R)-beta Pro(2)-Trp(3)-(2-furyl)Map(4) (analogue 12) displayed the highest affinity toward MOR, in the picomolar range (K-i(mu) = 3.72 pM). Forskolin-induced cAMP accumulation assays indicated that this analogue displayed an extremely high agonistic potency, in the subpicomolar range (EC50 = 0.0421 pM, E-max = 99.5%). This compound also displayed stronger in vivo antinociceptive activity after iv administration when compared to morphine in the tail-flick test, which indicates that this analogue was able to cross the blood-brain barrier.

  DOI：

  10.1021/jm400195y

文献信息

• A New Class of Highly Potent and Selective Endomorphin-1 Analogues Containing α-Methylene-β-aminopropanoic Acids (Map)
  作者：Yuan Wang、Yanhong Xing、Xin Liu、Hong Ji、Ming Kai、Zongyao Chen、Jing Yu、Depeng Zhao、Hui Ren、Rui Wang

  DOI：10.1021/jm300664y

  日期：2012.7.12

  A new class of endomorphin-1 (EM-1) analogues were synthesized by introduction of novel unnatural alpha-methylene-beta-amino acids (Map) at position 3 or/and position 4. Their binding and functional activity, metabolic stability, and antinociceptive activity were determined and compared. Most of these analogues showed high affinities for the mu-opioid receptor and an increased stability in mouse brain homogenates compared with EM-1. Examination of cAMP accumulation and ERK1/2 phosphorylation in HEK293 cells confirmed the agonist properties of these analogues. Among these new analogues, H-Tyr-Pro-Trp-(2-furyl)Map-NH2 (analogue 12) exhibited the highest binding potency (K-i(mu) = 0.221 nM) and efficacy (EC50 = 0.0334 nM, E-max = 97.14%). This analogue also displayed enhanced antinociceptive activity in vivo in comparison to EM-1. Molecular modeling approaches were then carried out to demonstrate the interaction pattern of these analogues with the opioid receptors. We found that, compared to EM-1, the incorporation of our synthesized Map at position 4 would bring the analogue to a closer binding mode with the mu-opioid receptor.