(±)-4-((3-((1-benzylpiperidin-4-yl)methyl)-1-(isoquinolin-5-ylmethyl)-2,5-dioxoimidazolidin-4-yl)methyl)phenyl isoquinoline-5-sulfonate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (±)-4-((3-((1-benzylpiperidin-4-yl)methyl)-1-(isoquinolin-5-ylmethyl)-2,5-dioxoimidazolidin-4-yl)methyl)phenyl isoquinoline-5-sulfonate
• 英文别名: [4-[[3-[(1-Benzylpiperidin-4-yl)methyl]-1-(isoquinolin-5-ylmethyl)-2,5-dioxoimidazolidin-4-yl]methyl]phenyl] isoquinoline-5-sulfonate；[4-[[3-[(1-benzylpiperidin-4-yl)methyl]-1-(isoquinolin-5-ylmethyl)-2,5-dioxoimidazolidin-4-yl]methyl]phenyl] isoquinoline-5-sulfonate
• 化学式: C₄₂H₃₉N₅O₅S
• 分子量: 725.868
• InChiKey: YYGFRZOBIIQIRV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  53
• 可旋转键数：
  11
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  121
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  Boc-L-酪氨酸甲酯 在 cesium bicarbonate 、 三乙酰氧基硼氢化钠 、 sodium hydride 、 溶剂黄146 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 41.0h， 生成 (±)-4-((3-((1-benzylpiperidin-4-yl)methyl)-1-(isoquinolin-5-ylmethyl)-2,5-dioxoimidazolidin-4-yl)methyl)phenyl isoquinoline-5-sulfonate
  参考文献：
  名称：

  Discovery of Novel 2,5-Dioxoimidazolidine-Based P2X₇ Receptor Antagonists as Constrained Analogues of KN62

  摘要：

  Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1 beta ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1 beta ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.

  DOI：

  10.1021/jm500324g

文献信息

• Discovery of Novel 2,5-Dioxoimidazolidine-Based P2X₇ Receptor Antagonists as Constrained Analogues of KN62
  作者：Jin-Hee Park、Ga-Eun Lee、So-Deok Lee、Tran Thi Hien、Sujin Kim、Jin Won Yang、Joong-Heui Cho、Hyojin Ko、Sung-Chul Lim、Yoon-Gyoon Kim、Keon-Wook Kang、Yong-Chul Kim

  DOI：10.1021/jm500324g

  日期：2015.3.12

  Novel 2,5-dioxoimidazolidine-based conformationally constrained analogues of KN62 (1) were developed as P2X7 receptor (P2X7R) antagonists using a rigidification strategy of the tyrosine backbone of 1. SAR analysis of the 2,5-dioxoimidazolidine scaffold indicated that piperidine substitution at the N3 position and no substitution at N1 position were preferable. Further optimization of the substituents at the piperidine nitrogen and the spacer around the skeleton resulted in several superior antagonists to 1, including 1-adamantanecarbonyl analogue 21i (IC50 = 23 nM in ethidium uptake assay; IC50 = 14 nM in IL-1 beta ELISA assay) and (3-CF3-4-Cl)benzoyl analogue (-)-21w (54 nM in ethidium uptake assay; 9 nM in IL-1 beta ELISA assay), which was more potent than the corresponding (+) isomer. Compound 21w displayed potent inhibitory activity in an ex vivo model of LTP-induced pain signaling in the spinal cord and significant anti-inflammatory activity in in vivo models of carrageenan-induced paw edema and type II collagen-induced joint arthritis.