[5-(1-cyclopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-ylmethanone | 1160606-00-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: [5-(1-cyclopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-ylmethanone
• 英文别名: (5-(1-cyclopropylpiperidin-4-yloxy)-1-(2,2,2-trifluoroethyl)-1H-indol-2-yl)(morpholino)methanone；[5-(1-cyclopropylpiperidin-4-yl)oxy-1-(2,2,2-trifluoroethyl)indol-2-yl]-morpholin-4-ylmethanone
• CAS: 1160606-00-7
• 化学式: C₂₃H₂₈F₃N₃O₃
• 分子量: 451.489
• InChiKey: JFVOIMDJWFZWKP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  46.9
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  1-乙氧基-1-三甲硅氧基环丙烷 、 morpholin-4-yl-[5-(piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-methanone trifluoroacetic acid salt 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 四氢呋喃 为溶剂， 反应 20.0h， 以45%的产率得到[5-(1-cyclopropyl-piperidin-4-yloxy)-1-(2,2,2-trifluoro-ethyl)-1H-indol-2-yl]-morpholin-4-ylmethanone
  参考文献：
  名称：

  5-Hydroxyindole-2-carboxylic Acid Amides: Novel Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity

  摘要：

  Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H3R) in the regulation of food intake and body weight and the potential therapeutic effect Of H3R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds. the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H-3 inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)1H-indol-2-yl]-methanone 36 are detailed.

  DOI：

  10.1021/jm900409x

文献信息

• 5-Hydroxyindole-2-carboxylic Acid Amides: Novel Histamine-3 Receptor Inverse Agonists for the Treatment of Obesity
  作者：Pascale David Pierson、Alec Fettes、Christian Freichel、Silvia Gatti-McArthur、Cornelia Hertel、Jörg Huwyler、Peter Mohr、Toshito Nakagawa、Matthias Nettekoven、Jean-Marc Plancher、Susanne Raab、Hans Richter、Olivier Roche、Rosa María Rodríguez Sarmiento、Monique Schmitt、Franz Schuler、Tadakatsu Takahashi、Sven Taylor、Christoph Ullmer、Ruby Wiegand

  DOI：10.1021/jm900409x

  日期：2009.7.9

  Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease, and cancer. Several pieces of evidence across different species, including primates, underscore the implication of the histamine 3 receptor (H3R) in the regulation of food intake and body weight and the potential therapeutic effect Of H3R inverse agonists. A pharmacophore model, based on public information and validated by previous investigations, was used to design several potential scaffolds. Out of these scaffolds. the 5-hydroxyindole-2-carboxylic acid amide appeared to be of great potential as a novel series of H-3 inverse agonist. Extensive structure-activity relationships revealed the interconnectivity of microsomal clearance and hERG (human ether-a-go-go-related gene) affinity with lipophilicity, artificial membrane permeation, and basicity. This effort led to the identification of compounds reversing the (R)-alpha-methylhistamine-induced water intake increase in Wistar rats and, further, reducing food intake in diet-induced obese Sprague-Dawley rats. Of these, the biochemical, pharmacokinetic, and pharmacodynamic characteristics of (4,4-difluoropiperidin-1-yl)[1-isopropyl-5-(1-isopropylpiperidin-4-yloxy)1H-indol-2-yl]-methanone 36 are detailed.