benzyl N-[amino-[[4-[4-(1H-pyrrole-2-carbonylamino)piperidin-1-yl]-3-(trifluoromethyl)benzoyl]amino]methylidene]carbamate | 1393368-46-1

• 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: benzyl N-[amino-[[4-[4-(1H-pyrrole-2-carbonylamino)piperidin-1-yl]-3-(trifluoromethyl)benzoyl]amino]methylidene]carbamate
• CAS: 1393368-46-1
• 化学式: C₂₇H₂₇F₃N₆O₄
• 分子量: 556.544
• InChiKey: NRWISRGNMRQZRV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  40
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  142
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  benzyl N-[amino-[[4-[4-(1H-pyrrole-2-carbonylamino)piperidin-1-yl]-3-(trifluoromethyl)benzoyl]amino]methylidene]carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 以10 mg的产率得到N-[1-[4-(carbamimidoylcarbamoyl)-2-(trifluoromethyl)phenyl]piperidin-4-yl]-1H-pyrrole-2-carboxamide
  参考文献：
  名称：

  Identification of a Potent Sodium Hydrogen Exchanger Isoform 1 (NHE1) Inhibitor with a Suitable Profile for Chronic Dosing and Demonstrated Cardioprotective Effects in a Preclinical Model of Myocardial Infarction in the Rat

  摘要：

  Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.

  DOI：

  10.1021/jm300601d
• 作为产物：
  描述：

  methyl 4-[4-(1H-pyrrole-2-carbonylamino)piperidin-1-yl]-3-(trifluoromethyl)benzoate 在 2-氯-1-甲基吡啶碘化物 、 水 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 为溶剂， 反应 1.0h， 生成 benzyl N-[amino-[[4-[4-(1H-pyrrole-2-carbonylamino)piperidin-1-yl]-3-(trifluoromethyl)benzoyl]amino]methylidene]carbamate
  参考文献：
  名称：

  Identification of a Potent Sodium Hydrogen Exchanger Isoform 1 (NHE1) Inhibitor with a Suitable Profile for Chronic Dosing and Demonstrated Cardioprotective Effects in a Preclinical Model of Myocardial Infarction in the Rat

  摘要：

  Sodium-hydrogen exchanger isoform 1 (NHE1) is a ubiquitously expressed transmembrane ion channel responsible for intracellular pH regulation. During myocardial ischemia, low pH activates NHE1 and causes increased intracellular calcium levels and aberrant cellular processes, leading to myocardial stunning, arrhythmias, and ultimately cell damage and death. The role of NHE1 in cardiac injury has prompted interest in the development of NHE1 inhibitors for the treatment of heart failure. This report outlines our efforts to identify a compound suitable for once daily, oral administration with low drug-drug interaction potential starting from NHE1 inhibitor sabiporide. Substitution of a piperidine for the piperazine of sabiporide followed by replacement of the pyrrole moiety and subsequent optimization to improve potency and eliminate off-target activities resulted in the identification of N-[4-(1-acetyl-piperidin-4-yl)-3-trifluoromethyl-benzoyl]-guanidine (60). Pharmacological evaluation of 60 revealed a remarkable ability to prevent ischemic damage in an ex vivo model of ischemia reperfusion injury in isolated rat hearts.

  DOI：

  10.1021/jm300601d