N-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2,5-dichloro-nicotinamide | 865169-60-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: N-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2,5-dichloro-nicotinamide
• 英文别名: N-[1-(1,3-benzodioxol-5-ylmethyl)piperidin-4-yl]-2,5-dichloropyridine-3-carboxamide
• CAS: 865169-60-4
• 化学式: C₁₉H₁₉Cl₂N₃O₃
• 分子量: 408.284
• InChiKey: RHECTQPLXWOTCO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  63.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2,5-dichloro-nicotinamide 、 2-氨乙基异丙醚 以 乙腈 为溶剂， 反应 0.5h， 以31%的产率得到N-(1-benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-5-chloro-2-(2-isopropoxyethylamino)nicotinamide
  参考文献：
  名称：

  Screening for Cardiovascular Safety:  A Structure−Activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists

  摘要：

  An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor I (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (> 40 mu M) and brain (> 20 mu g/g) with < 15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHrl antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

  DOI：

  10.1021/jm0512286
• 作为产物：
  描述：

  2,5-二氯烟酸 在 盐酸 、 PS-DCC 、 MP-BH₃CN 、 1-羟基苯并三唑 作用下， 以 1,4-二氧六环 、 甲醇 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 N-(1-Benzo[1,3]dioxol-5-ylmethyl-piperidin-4-yl)-2,5-dichloro-nicotinamide
  参考文献：
  名称：

  Identification of ortho-amino benzamides and nicotinamides as MCHr1 antagonists

  摘要：

  Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50. (c) 2005 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2005.06.089

文献信息

• Identification of ortho-amino benzamides and nicotinamides as MCHr1 antagonists
  作者：Anil Vasudevan、Matthew J. LaMarche、Christopher Blackburn、Jennifer Lee Che、Courtney A. Luchaco-Cullis、Sujen Lai、Thomas H. Marsilje、Michael A. Patane、Andrew J. Souers、Derek Wodka、Bradley Geddes、Sumiao Chen、Seven Brodjian、Doug H. Falls、Brian D. Dayton、Eugene Bush、Michael Brune、Robin D. Shapiro、Kennan C. Marsh、Lisa E. Hernandez、Hing L. Sham、Christine A. Collins、Philip R. Kym

  DOI：10.1016/j.bmcl.2005.06.089

  日期：2005.10

  Several potent and efficacious MCHr1 antagonists containing an ortho-amino benzamide or nicotinamide chemotype have been identified, exemplified by 28 and 50. (c) 2005 Published by Elsevier Ltd.
• Screening for Cardiovascular Safety:  A Structure−Activity Approach for Guiding Lead Selection of Melanin Concentrating Hormone Receptor 1 Antagonists
  作者：Philip R. Kym、Andrew J. Souers、Thomas J. Campbell、John K. Lynch、Andrew S. Judd、Rajesh Iyengar、Anil Vasudevan、Ju Gao、Jennifer C. Freeman、Dariusz Wodka、Mathew Mulhern、Gang Zhao、Seble H. Wagaw、James J. Napier、Sevan Brodjian、Brian D. Dayton、Regina M. Reilly、Jason A. Segreti、Ryan M. Fryer、Lee C. Preusser、Glenn A. Reinhart、Lisa Hernandez、Kennan C. Marsh、Hing L. Sham、Christine A. Collins、James S. Polakowski

  DOI：10.1021/jm0512286

  日期：2006.4.1

  An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor I (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (> 40 mu M) and brain (> 20 mu g/g) with < 15% change in cardiovascular endpoints. As a result of these stringent requirements, lead optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHrl antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.