N,N-dimethyl-5-cholenamid-3β-yl N,N-diethylcarbamate | 1450593-74-4

• 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: N,N-dimethyl-5-cholenamid-3β-yl N,N-diethylcarbamate
• 英文别名: [(3S,8S,9S,10R,13R,14S,17R)-17-[(2R)-5-(dimethylamino)-5-oxopentan-2-yl]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-yl] N,N-diethylcarbamate
• CAS: 1450593-74-4
• 化学式: C₃₁H₅₂N₂O₃
• 分子量: 500.765
• InChiKey: CLSPAYXGNPNYFT-MIXBDBMTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3B-羟基-D5-胆烯酸 在 吡啶 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 生成 N,N-dimethyl-5-cholenamid-3β-yl N,N-diethylcarbamate
  参考文献：
  名称：

  Structure–activity relationship studies of Niemann-Pick type C1-like 1 (NPC1L1) ligands identified by screening assay monitoring pharmacological chaperone effect

  摘要：

  A number of hereditary diseases are caused by defective protein trafficking due to a folding defect resulting from point mutations in proteins. Ligands that bind to the folding intermediates of such mutant proteins and rescue their trafficking defects, known as pharmacological chaperones, have promise for the treatment of certain genetic diseases, including Fabry disease, cystic fibrosis, and Niemann-Pick disease type C. Here we show that this pharmacological chaperone effect can be used for ligand screening, that is, binding of candidate ligands can be detected by monitoring the ligand-mediated correction of a localization defect caused by artificially introduced point mutations of the protein of interest. Using this method, we discovered novel steroidal ligands of Niemann-Pick type C1-like 1 (NPC1L1), an intestinal cholesterol transporter that is the target of the cholesterol absorption inhibitor ezetimibe, and conducted structure-activity relationship studies. We also present data indicating that the binding site of the new ligands is distinct from both the N-terminal sterol-binding domain and the ezetimibe-binding site. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.022

文献信息

• Structure–activity relationship studies of Niemann-Pick type C1-like 1 (NPC1L1) ligands identified by screening assay monitoring pharmacological chaperone effect
  作者：Fumika Karaki、Kenji Ohgane、Kosuke Dodo、Yuichi Hashimoto

  DOI：10.1016/j.bmc.2013.06.022

  日期：2013.9

  A number of hereditary diseases are caused by defective protein trafficking due to a folding defect resulting from point mutations in proteins. Ligands that bind to the folding intermediates of such mutant proteins and rescue their trafficking defects, known as pharmacological chaperones, have promise for the treatment of certain genetic diseases, including Fabry disease, cystic fibrosis, and Niemann-Pick disease type C. Here we show that this pharmacological chaperone effect can be used for ligand screening, that is, binding of candidate ligands can be detected by monitoring the ligand-mediated correction of a localization defect caused by artificially introduced point mutations of the protein of interest. Using this method, we discovered novel steroidal ligands of Niemann-Pick type C1-like 1 (NPC1L1), an intestinal cholesterol transporter that is the target of the cholesterol absorption inhibitor ezetimibe, and conducted structure-activity relationship studies. We also present data indicating that the binding site of the new ligands is distinct from both the N-terminal sterol-binding domain and the ezetimibe-binding site. (C) 2013 Elsevier Ltd. All rights reserved.