benzyl N2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-N5-(3-hydroxypyridin-2-yl)-L-glutaminate | 1243613-67-3

• 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: benzyl N2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-N5-(3-hydroxypyridin-2-yl)-L-glutaminate
• CAS: 1243613-67-3
• 化学式: C₄₁H₅₇N₃O₇
• 分子量: 703.919
• InChiKey: AFNPYQRXZZNWED-VXIFXTAJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.14
• 重原子数：
  51.0
• 可旋转键数：
  12.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  158.08
• 氢给体数：
  5.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  benzyl N2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-N5-(3-hydroxypyridin-2-yl)-L-glutaminate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 生成 N2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-N5-(3-hydroxypyridin-2-yl)-L-glutamine
  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：

  1-benzyl L-glutamate 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 benzyl N2-((R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoyl)-N5-(3-hydroxypyridin-2-yl)-L-glutaminate
  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