5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2S)-2-hydroxycyclohexyl]-3-pyridine carboxamide | 1493777-56-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2S)-2-hydroxycyclohexyl]-3-pyridine carboxamide
• 英文别名: 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2S)-2-hydroxycyclohexyl]pyridine-3-carboxamide
• CAS: 1493777-56-2
• 化学式: C₂₂H₂₅ClN₂O₃
• 分子量: 400.905
• InChiKey: IRNGVYZGPNAVHN-UXHICEINSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  71.4
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-溴-6-羟基烟酸 在 喹啉 、 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 lithium hydroxide monohydrate 、 1-氯-N,N,2-三甲基丙烯胺 、 sodium carbonate 、 potassium hydroxide 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 二甲基亚砜 、 甲苯 为溶剂， 反应 7.0h， 生成 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-N-[(1R,2S)-2-hydroxycyclohexyl]-3-pyridine carboxamide
  参考文献：
  名称：

  6-Alkoxy-5-aryl-3-pyridinecarboxamides, a New Series of Bioavailable Cannabinoid Receptor Type 1 (CB1) Antagonists Including Peripherally Selective Compounds

  摘要：

  We identified 6-alkoxy-5-aryl-3-pyridinecarboxamides as potent CB1 receptor antagonists with high selectivity over CB2 receptors. The series was optimized to reduce lipophilicity compared to rimonabant to achieve peripherally active molecules with minimal central effects. Several compounds that showed high plasma exposures in rats were evaluated in vivo to probe the contribution of central vs peripheral CB1 agonism to metabolic improvement. Both rimonabant and 14g, a potent brain penetrant CB1 receptor antagonist, significantly reduced the rate of body weight gain. However, 14h, a molecule with markedly reduced brain exposure, had no significant effect on body weight. PK studies confirmed similarly high exposure of both 14h and 14g in the periphery but 10-fold lower exposure in the brain for 14h. On the basis of these data, which are consistent with reported effects in tissue-specific CB1 receptor KO mice, we conclude that the metabolic benefits of CB1 receptor antagonists are primarily centrally mediated as originally believed.

  DOI：

  10.1021/jm4010708

文献信息

• 6-Alkoxy-5-aryl-3-pyridinecarboxamides, a New Series of Bioavailable Cannabinoid Receptor Type 1 (CB1) Antagonists Including Peripherally Selective Compounds
  作者：Stephan Röver、Mirjana Andjelkovic、Agnès Bénardeau、Evelyne Chaput、Wolfgang Guba、Paul Hebeisen、Susanne Mohr、Matthias Nettekoven、Ulrike Obst、Wolfgang F. Richter、Christoph Ullmer、Pius Waldmeier、Matthew B. Wright

  DOI：10.1021/jm4010708

  日期：2013.12.27

  We identified 6-alkoxy-5-aryl-3-pyridinecarboxamides as potent CB1 receptor antagonists with high selectivity over CB2 receptors. The series was optimized to reduce lipophilicity compared to rimonabant to achieve peripherally active molecules with minimal central effects. Several compounds that showed high plasma exposures in rats were evaluated in vivo to probe the contribution of central vs peripheral CB1 agonism to metabolic improvement. Both rimonabant and 14g, a potent brain penetrant CB1 receptor antagonist, significantly reduced the rate of body weight gain. However, 14h, a molecule with markedly reduced brain exposure, had no significant effect on body weight. PK studies confirmed similarly high exposure of both 14h and 14g in the periphery but 10-fold lower exposure in the brain for 14h. On the basis of these data, which are consistent with reported effects in tissue-specific CB1 receptor KO mice, we conclude that the metabolic benefits of CB1 receptor antagonists are primarily centrally mediated as originally believed.