2-(2-methoxyphenyl)-8-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-2,8-diazaspiro[4.5]decane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-(2-methoxyphenyl)-8-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-2,8-diazaspiro[4.5]decane
• 英文别名: 2-(2-Methoxyphenyl)-8-[3-[(4-methyl-5-phenyl-1,2,4-triazol-3-yl)sulfanyl]propyl]-2,8-diazaspiro[4.5]decane；2-(2-methoxyphenyl)-8-[3-[(4-methyl-5-phenyl-1,2,4-triazol-3-yl)sulfanyl]propyl]-2,8-diazaspiro[4.5]decane
• 化学式: C₂₇H₃₅N₅OS
• 分子量: 477.674
• InChiKey: AKUFOSYLIYVIGY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  71.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2,8-二氮杂螺[4.5]癸烷-8-羧酸叔丁酯 在 tris-(dibenzylideneacetone)dipalladium(0) 、 caesium carbonate 、 三氟乙酸 、 sodium t-butanolate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 15.33h， 生成 2-(2-methoxyphenyl)-8-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)propyl)-2,8-diazaspiro[4.5]decane
  参考文献：
  名称：

  具有Arylated Diazaspiro Alkane核心的高选择性多巴胺D3受体拮抗剂。

  摘要：

  合成了一系列具有重氮杂螺烷核心的有效和选择性D 3受体（D 3 R）类似物。化合物的放射性配体结合11，14，图15A，和图15C显示有利d 3 R有着亲和性（ķ我= 12-25.6 1nM）和分别为d高度选择性3 - [R VS d 3 R（范围从264-〜905倍）。使用我们先前报道的10–20分钟台式C–N交叉偶联方法，可以实现这些新颖的配体体系结构的变化，从而提供了多种芳基化的diazaspiro前体。

  DOI：

  10.1021/acs.jmedchem.7b01248

文献信息

• Highly Selective Dopamine D₃ Receptor Antagonists with Arylated Diazaspiro Alkane Cores
  作者：Sean W. Reilly、Suzy Griffin、Michelle Taylor、Kristoffer Sahlholm、Chi-Chang Weng、Kuiying Xu、Daniel A. Jacome、Robert R. Luedtke、Robert H. Mach

  DOI：10.1021/acs.jmedchem.7b01248

  日期：2017.12.14

  A series of potent and selective D3 receptor (D3R) analogues with diazaspiro alkane cores were synthesized. Radioligand binding of compounds 11, 14, 15a, and 15c revealed favorable D3R affinity (Ki = 12–25.6 nM) and were highly selective for D3R vs D3R (ranging from 264- to 905-fold). Variation of these novel ligand architectures can be achieved using our previously reported 10–20 min benchtop C–N

  合成了一系列具有重氮杂螺烷核心的有效和选择性D 3受体（D 3 R）类似物。化合物的放射性配体结合11，14，图15A，和图15C显示有利d 3 R有着亲和性（ķ我= 12-25.6 1nM）和分别为d高度选择性3 - [R VS d 3 R（范围从264-〜905倍）。使用我们先前报道的10–20分钟台式C–N交叉偶联方法，可以实现这些新颖的配体体系结构的变化，从而提供了多种芳基化的diazaspiro前体。
• Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D₃ Receptor (D₃R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs)
  作者：Sean W. Reilly、Aladdin A. Riad、Chia-Ju Hsieh、Kristoffer Sahlholm、Daniel A. Jacome、Suzy Griffin、Michelle Taylor、Chi-Chang Weng、Kuiying Xu、Nathan Kirschner、Robert R. Luedtke、Christopher Parry、Shipra Malhotra、John Karanicolas、Robert H. Mach

  DOI：10.1021/acs.jmedchem.9b00412

  日期：2019.5.23

  Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)thio)-propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D-3 receptor (D3R) affinity (D3R K-i = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R K-i = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R K-i = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity (K-i = 2.7 mu M). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R K-i = 23.9 nM), 1 was found to be more selective for the D3R among D-1- and D-2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.