N-[5-methanesulfonyl-4-(1-propionyl-piperidin-4-yl)-2-methylbenzoyl]guanidine trifluoroacetic acid | 1204328-09-5

• 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: N-[5-methanesulfonyl-4-(1-propionyl-piperidin-4-yl)-2-methylbenzoyl]guanidine trifluoroacetic acid
• 英文别名: N-(diaminomethylidene)-2-methyl-5-methylsulfonyl-4-(1-propanoylpiperidin-4-yl)benzamide;2,2,2-trifluoroacetic acid
• CAS: 1204328-09-5
• 化学式: C₂HF₃O₂*C₁₈H₂₆N₄O₄S
• 分子量: 508.519
• InChiKey: PREMPIMCEMQJGN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.56
• 重原子数：
  34
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  182
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  4-溴-2-甲基苯甲酸 在 盐酸 、 氯磺酸 、 platinum(IV) oxide 、 四(三苯基膦)钯 、 lithium hydroxide monohydrate 、 10% Pd/C 、 2-氯-1-甲基吡啶碘化物 、 氢气 、 碳酸氢钠 、 potassium carbonate 、 溶剂黄146 、 N,N'-羰基二咪唑 、 sodium sulfite 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N-甲基吡咯烷酮 、 甲醇 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 N-[5-methanesulfonyl-4-(1-propionyl-piperidin-4-yl)-2-methylbenzoyl]guanidine trifluoroacetic acid
  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

文献信息

• 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
  作者：John D. Huber、Jörg Bentzien、Stephen J. Boyer、Jennifer Burke、Stéphane De Lombaert、Christian Eickmeier、Xin Guo、James V. Haist、Eugene R. Hickey、Paul Kaplita、Morris Karmazyn、Raymond Kemper、Charles A. Kennedy、Thomas Kirrane、Jeffrey B. Madwed、Elizabeth Mainolfi、Nelamangara Nagaraja、Fariba Soleymanzadeh、Alan Swinamer、Anne B. Eldrup

  DOI：10.1021/jm300601d

  日期：2012.8.23

  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.