2-(2-(5-fluoropyrimidin-2-yl)ethyl)-4-hydroxy-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide | 1392000-77-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异吲哚及其衍生物
• 英文名称: 2-(2-(5-fluoropyrimidin-2-yl)ethyl)-4-hydroxy-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide
• 英文别名: 2-[2-(5-fluoropyrimidin-2-yl)ethyl]-4-hydroxy-3-oxo-N-[[4-(trifluoromethoxy)phenyl]methyl]-1H-isoindole-1-carboxamide
• CAS: 1392000-77-9
• 化学式: C₂₃H₁₈F₄N₄O₄
• 分子量: 490.414
• InChiKey: LPQIVQULTGLWTO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  2-(2-(5-fluoropyrimidin-2-yl)ethyl)-4-methoxy-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 以28.3%的产率得到2-(2-(5-fluoropyrimidin-2-yl)ethyl)-4-hydroxy-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide
  参考文献：
  名称：

  3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na_V1.7 with Efficacy in Rat Pain Models

  摘要：

  The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.

  DOI：

  10.1021/jm300623u

文献信息

• 3-Oxoisoindoline-1-carboxamides: Potent, State-Dependent Blockers of Voltage-Gated Sodium Channel Na_V1.7 with Efficacy in Rat Pain Models
  作者：Istvan Macsari、Yevgeni Besidski、Gabor Csjernyik、Linda I. Nilsson、Lars Sandberg、Ulrika Yngve、Kristofer Åhlin、Tjerk Bueters、Anders B. Eriksson、Per-Eric Lund、Elisabet Venyike、Sandra Oerther、Karin Hygge Blakeman、Lei Luo、Per I. Arvidsson

  DOI：10.1021/jm300623u

  日期：2012.8.9

  The voltage-gated sodium channel Na(V)1.7 is believed to be a critical mediator of pain sensation based on clinical genetic studies and pharmacological results. Clinical utility of nonselective sodium channel blockers is limited due to serious adverse drug effects. Here, we present the optimization, structure activity relationships, and in vitro and in vivo characterization of a novel series of Na(V)1.7 inhibitors based on the oxoisoindoline core. Extensive studies with focus on optimization of Na(V)1.7 potency, selectivity over Na(V)1.5, and metabolic stability properties produced several interesting oxoisoindoline carboxamides (16A, 26B, 28, 51, 60, and 62) that were further characterized. The oxoisoindoline carboxamides interacted with the local anesthetics binding site. In spite of this, several compounds showed functional selectivity versus Na(V)1.5 of more than 100-fold. This appeared to be a combination of subtype and state-dependent selectivity. Compound 28 showed concentration-dependent inhibition of nerve injury-induced ectopic in an ex vivo DRG preparation from SNL rats. Compounds 16A and 26B demonstrated concentration-dependent efficacy in preclinical behavioral pain models. The oxoisoindoline carboxamides series described here may be valuable for further investigations for pain therapeutics.