3-amino-5-chloro-6-methoxy-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-4-methylthieno[2,3-b]pyridine-2-carboxamide | 1610591-91-7

• 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: 3-amino-5-chloro-6-methoxy-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-4-methylthieno[2,3-b]pyridine-2-carboxamide
• 英文别名: 3-amino-5-chloro-6-methoxy-N-[2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl]-4-methylthieno[2,3-b]pyridine-2-carboxamide
• CAS: 1610591-91-7
• 化学式: C₂₃H₂₈ClN₅O₃S
• 分子量: 490.026
• InChiKey: MAPGIJMBSHARKF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  121
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  ethyl 3-(1,3-dioxoisoindolin-2-yl)-6-methoxy-4-methylthieno[2,3-b]pyridine-2-carboxylate 在 盐酸 、 N-氯代丁二酰亚胺 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 一水合肼 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 3-amino-5-chloro-6-methoxy-N-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-4-methylthieno[2,3-b]pyridine-2-carboxamide
  参考文献：
  名称：

  Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D₂ Receptor

  摘要：

  Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D-2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.

  DOI：

  10.1021/jm500457x

文献信息

• Structure–Activity Relationships of Privileged Structures Lead to the Discovery of Novel Biased Ligands at the Dopamine D₂ Receptor
  作者：Monika Szabo、Carmen Klein Herenbrink、Arthur Christopoulos、J. Robert Lane、Ben Capuano

  DOI：10.1021/jm500457x

  日期：2014.6.12

  Biased agonism at GPCRs highlights the potential for the discovery and design of pathway-selective ligands and may confer therapeutic advantages to ligands targeting the dopamine D-2 receptor (D2R). We investigated the determinants of efficacy, affinity, and bias for three privileged structures for the D2R, exploring changes to linker length and incorporation of a heterocyclic unit. Profiling the compounds in two signaling assays (cAMP and pERK1/2) allowed us to identify and quantify determinants of biased agonism at the D2R. Substitution on the phenylpiperazine privileged structures (2-methoxy vs 2,3-dichloro) influenced bias when the thienopyridine heterocycle was absent. Upon inclusion of the thienopyridine unit, the substitution pattern (4,6-dimethyl vs 5-chloro-6-methoxy-4-methyl) had a significant effect on bias that overruled the effect of the phenylpiperazine substitution pattern. This latter observation could be reconciled with an extended binding mode for these compounds, whereby the interaction of the heterocycle with a secondary binding pocket may engender bias.