N-{2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-1-yl]-propyl}-2-(3-trifluoromethyl-phenylamino)-nicotinamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-{2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-1-yl]-propyl}-2-(3-trifluoromethyl-phenylamino)-nicotinamide
• 英文别名: 2-[[3-(Trifluoromethyl)phenyl]amino]-N-[3-[4-(2-isopropoxyphenyl)piperazine-1-yl]-2-hydroxypropyl]-3-pyridinecarboxamide；N-[2-hydroxy-3-[4-(2-propan-2-yloxyphenyl)piperazin-1-yl]propyl]-2-[3-(trifluoromethyl)anilino]pyridine-3-carboxamide
• 化学式: C₂₉H₃₄F₃N₅O₃
• 分子量: 557.616
• InChiKey: ABVHNZOBDMKCFO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  40
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  90
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-(1-methylethoxy)phenyl-1-piperazine 在 4-二甲氨基吡啶 、 palladium on activated charcoal 盐酸 、 氢气 、 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 作用下， 以 N-甲基吡咯烷酮 、 甲醇 、 二氯甲烷 、 水 为溶剂， 20.0~100.0 ℃ 、344.74 kPa 条件下， 反应 70.0h， 生成 N-{2-Hydroxy-3-[4-(2-isopropoxy-phenyl)-piperazin-1-yl]-propyl}-2-(3-trifluoromethyl-phenylamino)-nicotinamide
  参考文献：
  名称：

  Design, synthesis and biological evaluation of pyridine-phenylpiperazines: A novel series of potent and selective α1a-adrenergic receptor antagonist

  摘要：

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers displayed comparable potency and better selectivity at alpha(1a)-AR. The S-hydroxy enantiomer 17 (K-i = 0.79 nM; alpha(1b)/alpha(1a) = 800; alpha(1d)/alpha(1a) = 104) was slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1b)/alpha(1a) = 15, alpha(1d)/alpha(1a) = 1.4). Compound 17 displayed higher selectivity in inhibiting rat prostate contraction over rat aorta contraction and also exhibited a higher degree of uroselectivity than tamsulosin in the anesthetized dog model. (C) 2000 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(00)00151-6

文献信息

• Design, synthesis and biological evaluation of pyridine-phenylpiperazines: A novel series of potent and selective α1a-adrenergic receptor antagonist
  作者：Gee-Hong Kuo、Catherine Prouty、William V Murray、Virginia Pulito、Linda Jolliffe、Peter Cheung、Sally Varga、Mary Evangelisto、Charles Shaw

  DOI：10.1016/s0968-0896(00)00151-6

  日期：2000.9

  Beginning from the screening hit and literature alpha(1)-adrenergic compounds, a hybridized basic skeleton A was proposed as the pharmacophore for potent and selective alpha(1a)-AR antagonists. Introduction of a hydroxy group to increase the flexibility afforded B which served as the screening model and resulted in the identification of the second-generation lead 1. Using the Topliss approach, a number of potent and selective alpha(1a)-AR antagonists were discovered. In all cases, binding affinity and selectivity at the alpha(1a)-AR of S-hydroxy enantiomers were higher than the R-hydroxy enantiomers. As compared to the des-hydroxy analogues, the S-hydroxy enantiomers displayed comparable potency and better selectivity at alpha(1a)-AR. The S-hydroxy enantiomer 17 (K-i = 0.79 nM; alpha(1b)/alpha(1a) = 800; alpha(1d)/alpha(1a) = 104) was slightly less potent but much more selective at alpha(1a)-AR than tamsulosin (K-i = 0.13 nM, alpha(1b)/alpha(1a) = 15, alpha(1d)/alpha(1a) = 1.4). Compound 17 displayed higher selectivity in inhibiting rat prostate contraction over rat aorta contraction and also exhibited a higher degree of uroselectivity than tamsulosin in the anesthetized dog model. (C) 2000 Elsevier Science Ltd. All rights reserved.