1-(2-(4-((dimethylamino)methyl)-2-methylphenyl)-2-oxoethyl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one | 1453499-18-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(2-(4-((dimethylamino)methyl)-2-methylphenyl)-2-oxoethyl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one
• 英文别名: 1-[2-[4-[(Dimethylamino)methyl]-2-methylphenyl]-2-oxoethyl]-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-one；1-[2-[4-[(dimethylamino)methyl]-2-methylphenyl]-2-oxoethyl]-4-[(5-fluoropyridin-2-yl)methoxy]pyridin-2-one
• CAS: 1453499-18-7
• 化学式: C₂₃H₂₄FN₃O₃
• 分子量: 409.46
• InChiKey: QKLFVKUALMUOSG-UHFFFAOYSA-N

物化性质

• 沸点：
  616.1±55.0 °C(predicted)
• 密度：
  1.26±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  30
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  62.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one 在 三溴化磷 、 caesium carbonate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 1-(2-(4-((dimethylamino)methyl)-2-methylphenyl)-2-oxoethyl)-4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one
  参考文献：
  名称：

  Design, synthesis and evaluation of MCH receptor 1 antagonists—Part III: Discovery of pre-clinical development candidate BI 186908

  摘要：

  Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.05.065

文献信息

• Design, synthesis and evaluation of MCH receptor 1 antagonists—Part III: Discovery of pre-clinical development candidate BI 186908
  作者：Thorsten Oost、Armin Heckel、Jörg T. Kley、Thorsten Lehmann、Stephan Müller、Gerald J. Roth、Klaus Rudolf、Kirsten Arndt、Ralph Budzinski、Martin Lenter、Ralf R.H. Lotz、Gerd-Michael Maier、Michael Markert、Leo Thomas、Dirk Stenkamp

  DOI：10.1016/j.bmcl.2015.05.065

  日期：2015.8

  Although overweight and obesity are highly prevalent conditions, options to treat them are still very limited. As part of our search for safe and effective MCH-R1 antagonists for the treatment of obesity, two series of pyridones and pyridazinones were evaluated. Optimization was aimed at improving DMPK properties by increasing metabolic stability and improving the safety profile by reducing inhibition of the hERG channel and reducing the potential to induce phospholipidosis. Steric shielding of a labile keto moiety with an ortho-methyl group and fine-tuning of the polarity in several parts of the molecule resulted in BI 186908 (11g), a potent and selective MCH-R1 antagonist with favorable DMPK and CMC properties. Chronic administration of BI 186908 resulted in significant body weight reduction comparable to sibutramine in a 4 week diet-induced obesity model in rats. Based on its favorable safety profile, BI 186908 was advanced to pre-clinical development. (C) 2015 Elsevier Ltd. All rights reserved.