3-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3-[4-(2-(2-naphthyl)-2-oxoethoxy)-3-methylphenyl]pentane

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3-[4-(2-(2-naphthyl)-2-oxoethoxy)-3-methylphenyl]pentane
• 英文别名: 3,3-Dimethyl-1-[2-methyl-4-[3-[3-methyl-4-(2-naphthalen-2-yl-2-oxoethoxy)phenyl]pentan-3-yl]phenoxy]butan-2-one
• 化学式: C₃₇H₄₂O₄
• 分子量: 550.738
• InChiKey: GBPHYCFDBYXKKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.3
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-溴代-2-乙酰基萘 、 1-(4-(3-(4-hydroxy-3-methylphenyl)pentan-3-yl)-2-methylphenoxy)-3,3-dimethylbutan-2-one 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 以50%的产率得到3-[4-(2-oxo-3,3-dimethylbutoxy)-3-methylphenyl]-3-[4-(2-(2-naphthyl)-2-oxoethoxy)-3-methylphenyl]pentane
  参考文献：
  名称：

  Structure-Based Design of Selective Agonists for a Rickets-Associated Mutant of the Vitamin D Receptor

  摘要：

  The nuclear and steroid hormone receptors function as ligand-depenclent transcriptional regulators of diverse sets of genes associated with development and homeostasis. Mutations to the vitamin D receptor (VDR), a member of the nuclear and steroid hormone receptor family, have been linked to human vitamin D-resistant rickets (hVDRR) and result in high serum 1,25(OH)(2)D-3 concentrations and severe bone underdevelopment. Several hVDRR-associated mutants have been localized to the ligand binding domain of VDR and cause a reduction in or loss of ligand binding and ligand-dependent transactivation function. The missense mutation Arg274 --> Leu causes a > 1 000-fold reduction in 1,25(OH)(2)D-3 responsiveness and is, therefore, no longer regulated by physiological concentrations of the hormone. In this study, computer-aided molecular design was used to generate a focused library of nonsteroidal analogues of the VDR agonist LG190155 that were uniquely designed to complement the Arg274 --> Leu associated with hVDRR. Half of the designed analogues exhibit substantial activity in the hVDRR-associated mutant, whereas none of the structurally similar control compounds exhibited significant activity. The seven most active designed analogues were more than 16 to 526 times more potent than 1,25(OH)(2)D-3 in the mutant receptor (EC50 = 3.3-121 nM). Significantly, the analogues are selective for the nuclear VDR and did not stimulate cellular calcium influx, which is associated with activation of the membrane-associated vitamin D receptor.

  DOI：

  10.1021/ja0268377

文献信息

• Structure-Based Design of Selective Agonists for a Rickets-Associated Mutant of the Vitamin D Receptor
  作者：Steve L. Swann、Joel Bergh、Mary C. Farach-Carson、Cory A. Ocasio、John T. Koh

  DOI：10.1021/ja0268377

  日期：2002.11.1

  The nuclear and steroid hormone receptors function as ligand-depenclent transcriptional regulators of diverse sets of genes associated with development and homeostasis. Mutations to the vitamin D receptor (VDR), a member of the nuclear and steroid hormone receptor family, have been linked to human vitamin D-resistant rickets (hVDRR) and result in high serum 1,25(OH)(2)D-3 concentrations and severe bone underdevelopment. Several hVDRR-associated mutants have been localized to the ligand binding domain of VDR and cause a reduction in or loss of ligand binding and ligand-dependent transactivation function. The missense mutation Arg274 --> Leu causes a > 1 000-fold reduction in 1,25(OH)(2)D-3 responsiveness and is, therefore, no longer regulated by physiological concentrations of the hormone. In this study, computer-aided molecular design was used to generate a focused library of nonsteroidal analogues of the VDR agonist LG190155 that were uniquely designed to complement the Arg274 --> Leu associated with hVDRR. Half of the designed analogues exhibit substantial activity in the hVDRR-associated mutant, whereas none of the structurally similar control compounds exhibited significant activity. The seven most active designed analogues were more than 16 to 526 times more potent than 1,25(OH)(2)D-3 in the mutant receptor (EC50 = 3.3-121 nM). Significantly, the analogues are selective for the nuclear VDR and did not stimulate cellular calcium influx, which is associated with activation of the membrane-associated vitamin D receptor.