glutamic acid CDCA amide | 892403-44-0

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: glutamic acid CDCA amide
• 英文别名: glu-CDCA
• CAS: 892403-44-0
• 化学式: C₃₆H₅₃NO₇
• 分子量: 611.819
• InChiKey: MBOBPGRODXGOKT-FJDOYGHDSA-N

物化性质

• 沸点：
  784.9±60.0 °C(Predicted)
• 密度：
  1.182±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.49
• 重原子数：
  44.0
• 可旋转键数：
  11.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  133.16
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  2,6-二氨基吡啶 、 glutamic acid CDCA amide 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 生成
  参考文献：
  名称：

  Structural Requirements of the ASBT by 3D-QSAR Analysis Using Aminopyridine Conjugates of Chenodeoxycholic Acid

  摘要：

  The human apical sodium-dependent bile acid transporter (ASBT) is a validated drug target and can be employed to increase oral bioavailability of various drug conjugates. The aim of the present study was to investigate the chemical space around the 24-position of bile acids that influences both inhibition and uptake by the transporter. A series of 27 aminopyridine and aminophenol conjugates of glutamyl-chenodeoxycholate were synthesized and their ASBT inhibition and transport kinetics (parametrized as K-i, K-t and J(max)) measured using stably transfected ASBT-MDCK cells. All conjugates were potent ASBT inhibitors. Monoanionic conjugates exhibited higher inhibition potency than neutral conjugates. However, neutral conjugates and chloro-substituted monoanionic conjugates were not substrates, or at least not apparent substrates. Kinetic analysis of substrates indicated that similar values for K-i and K-t implicate substrate binding to ASBT as the rate-limiting step. Using 3D-QSAR, four inhibition models and one transport efficiency model were developed. Steric fields dominated in CoMFA models, whereas hydrophobic fields dominated CoMSIA models. The inhibition models showed that a hydrophobic or bulky substitute on the 2 or 6 position of a 3-aminopyridine ring enhanced activity, while a hydrophobic group on the 5 position was detrimental. Overall, steric and hydrophobic features around the 24 position of the sterol nucleus strongly influenced bile acid conjugate interaction with ASBT. The relative location of the pyridine nitrogen and substituent groups also modulated binding.

  DOI：

  10.1021/bc100273w
• 作为产物：
  描述：

  鹅去氧胆酸 在 1-羟基苯并三唑 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 glutamic acid CDCA amide
  参考文献：
  名称：

  Structural Requirements of the ASBT by 3D-QSAR Analysis Using Aminopyridine Conjugates of Chenodeoxycholic Acid

  摘要：

  The human apical sodium-dependent bile acid transporter (ASBT) is a validated drug target and can be employed to increase oral bioavailability of various drug conjugates. The aim of the present study was to investigate the chemical space around the 24-position of bile acids that influences both inhibition and uptake by the transporter. A series of 27 aminopyridine and aminophenol conjugates of glutamyl-chenodeoxycholate were synthesized and their ASBT inhibition and transport kinetics (parametrized as K-i, K-t and J(max)) measured using stably transfected ASBT-MDCK cells. All conjugates were potent ASBT inhibitors. Monoanionic conjugates exhibited higher inhibition potency than neutral conjugates. However, neutral conjugates and chloro-substituted monoanionic conjugates were not substrates, or at least not apparent substrates. Kinetic analysis of substrates indicated that similar values for K-i and K-t implicate substrate binding to ASBT as the rate-limiting step. Using 3D-QSAR, four inhibition models and one transport efficiency model were developed. Steric fields dominated in CoMFA models, whereas hydrophobic fields dominated CoMSIA models. The inhibition models showed that a hydrophobic or bulky substitute on the 2 or 6 position of a 3-aminopyridine ring enhanced activity, while a hydrophobic group on the 5 position was detrimental. Overall, steric and hydrophobic features around the 24 position of the sterol nucleus strongly influenced bile acid conjugate interaction with ASBT. The relative location of the pyridine nitrogen and substituent groups also modulated binding.

  DOI：

  10.1021/bc100273w

文献信息

• Synthesis and In Vitro Evaluation of Gabapentin Prodrugs that Target the Human Apical Sodium-Dependent Bile Acid Transporter (hASBT)
  作者：Rana Rais、Steven Fletcher、James E. Polli

  DOI：10.1002/jps.22332

  日期：2011.3

  Gabapentin is a zwitterionic drug that exhibits low and variable oral absorption at therapeutic doses. The human apical sodium-dependent bile acid transporter (hASBT; SLC10A2) is a potential prodrug target to increase oral drug absorption. The objective was to evaluate several bile acid conjugates of gabapentin as potential prodrugs that target hASBT. Five analogues were synthesized and varied in ionic

  加巴喷丁是一种两性离子药物，在治疗剂量下口服吸收低而可变。人类根尖钠依赖性胆汁酸转运蛋白（hASBT； SLC10A2）是增加口服药物吸收的潜在前药靶标。目的是评估加巴喷丁的几种胆汁酸缀合物作为靶向hASBT的潜在前药。合成了五种类似物，其离子性质以及在胆汁酸和药物之间是否存在谷氨酸连接基的情况都不同。使用稳定转染的hASBT-MDCK细胞评估类似物的抑制和摄取特性。这两种单阴离子共轭物是有效的hASBT底物，具有高亲和力（K（m）为16.3和5.99μM）和高容量（V（max）为0.656和0.842 pmol / cm（2）/ s）。双阴离子共轭物以中等效力抑制hASBT，但不是底物。两种单阴离子共轭物在Caco-2匀浆和大鼠肝微粒体中被催化降解。每种药物均从前药中产生加巴喷丁。这两种结合物是加巴喷丁的新型前药，并说明了可设计用于靶向hASBT的前药。
• Molecular Switch Controlling the Binding of Anionic Bile Acid Conjugates to Human Apical Sodium-Dependent Bile Acid Transporter
  作者：Rana Rais、Chayan Acharya、Gasirat Tririya、Alexander D. MacKerell、James E. Polli

  DOI：10.1021/jm1003683

  日期：2010.6.24

  The human apical sodium-dependent bile acid transporter (hASBT) may serve as a prodrug target for oral drug absorption. Synthetic, biological, NMR, and computational approaches identified the structure−activity relationships of mono- and dianionic bile acid conjugates for hASBT binding. Experimental data combined with a conformationally sampled pharmacophore/QSAR modeling approach (CSP-SAR) predicted

  人顶端钠依赖性胆汁酸转运蛋白 (hASBT) 可作为口服药物吸收的前药靶点。合成、生物学、核磁共振和计算方法确定了单和双阴离子胆汁酸缀合物与 hASBT 结合的结构-活性关系。实验数据结合构象采样药效团/QSAR 建模方法 (CSP-SAR) 预测，胆烷骨架上的羟基与偶联物芳环上的酸基之间具有分子内氢键的双阴离子取代基增加了偶联物的疏水性并提高了结合亲和力。值得注意的是，该模型预测了构象分子开关的存在，其中通过单一位置控制的结合亲和力移动芳环上的羧酸根取代基。模型验证是通过在芳环附近插入一个亚甲基来有效移动羧酸盐的空间位置来进行的，从而导致结合亲和力的预测改变。这项工作说明构象是配体理化性质和配体与生物转运蛋白结合亲和力的决定因素。