(4aR,11R,11aS)-11-methyl-9-(trifluoromethyl)-2,3,4,4a,5,6,11,11a-octahydro-1H-pyrido[4,3-b]carbazole | 693823-71-1

• 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: (4aR,11R,11aS)-11-methyl-9-(trifluoromethyl)-2,3,4,4a,5,6,11,11a-octahydro-1H-pyrido[4,3-b]carbazole
• 英文别名: 9-(Trifluoromethyl)-11alpha-methyl-2,3,4,4abeta,5,6,11,11aalpha-octahydro-1H-pyrido[4,3-b]carbazole
• CAS: 693823-71-1
• 化学式: C₁₇H₁₉F₃N₂
• 分子量: 308.346
• InChiKey: KWSWMXVFUJMYOF-GIPNMCIBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  22
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  27.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (4aR,11R,11aS)-11-methyl-9-(trifluoromethyl)-2,3,4,4a,5,6,11,11a-octahydro-1H-pyrido[4,3-b]carbazole 、 四氢呋喃-3-羰酰氯 在 吡啶 作用下， 以 二氯甲烷 为溶剂， 生成
  参考文献：
  名称：

  Discovery of a novel series of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity

  摘要：

  A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.110
• 作为产物：
  描述：

  N-苄基哌啶酮 在 四氢吡咯 、 硫酸 、 palladium on activated charcoal 、 氢气 作用下， 以 1,4-二氧六环 、 乙醇 、 甲苯 为溶剂， 生成 (4aR,11R,11aS)-11-methyl-9-(trifluoromethyl)-2,3,4,4a,5,6,11,11a-octahydro-1H-pyrido[4,3-b]carbazole
  参考文献：
  名称：

  Discovery of a novel series of melanin-concentrating hormone receptor 1 antagonists for the treatment of obesity

  摘要：

  A new class of MCHR1 antagonists was discovered via a high-throughput screen. Optimization of the lead structure resulted in the identification of indole 10e. This compound possesses good pharmacokinetic properties across preclinical species and is efficacious in reducing food consumption in an MCH cannulated rat model and a cynomolgus monkey food consumption model. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.09.110

文献信息

• [EN] FUSED HETEROCYCLIC COMPOUNDS<br/>[FR] COMPOSES HETEROCYCLIQUES CONDENSES
  申请人：TULARIK INC

  公开号：WO2004043958A1

  公开（公告）日：2004-05-27

  Compounds, compositions and methods are provided that are useful in the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor. In particular, the compounds of the invention are useful in the treatment and/or prevention of eating disorders, obesity, anxiety disorders and mood disorders.

  提供了一种在治疗和/或预防由G蛋白偶联受体介导的疾病或紊乱方面有用的化合物、组合物和方法。特别是，本发明的化合物在治疗和/或预防进食紊乱、肥胖、焦虑症和情绪障碍方面是有用的。
• Discovery of a novel melanin concentrating hormone receptor 1 (MCHR1) antagonist with reduced hERG inhibition
  作者：Jeffrey T. Mihalic、Pingchen Fan、Xiaoqi Chen、Xi Chen、Ying Fu、Alykhan Motani、Lingming Liang、Michelle Lindstrom、Liang Tang、Jin-Long Chen、Juan Jaen、Kang Dai、Leping Li

  DOI：10.1016/j.bmcl.2012.04.006

  日期：2012.6

  identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several

  最初的SAR研究导致了新型有效的MCHR1拮抗剂2的鉴定。进一步分析后，发现化合物2是hERG钾通道的有效抑制剂，阻止了其进一步发展。该结构的其他优化导致发现了具有显着降低的hERG耐受性的有效MCHR1拮抗剂11。多项体内临床前心血管研究检查了QT延长，证实了hERG活性的降低。该化合物对MCHR1表现出良好的选择性，并且在整个临床前物种中均具有良好的药代动力学特性。化合物11在两种体内小鼠模型中，在减轻体重方面也是有效的。选择该化合物进行临床评估，并赋予其代码AMG 076。
• Stereoselective Synthesis of a MCHr1 Antagonist
  作者：Denise Andersen、Thomas Storz、Pingli Liu、Xin Wang、Leping Li、Pingchen Fan、Xiaoqi Chen、Alan Allgeier、Alain Burgos、Jason Tedrow、Jean Baum、Ying Chen、Rich Crockett、Liang Huang、Rashid Syed、Robert D. Larsen、Mike Martinelli

  DOI：10.1021/jo701894v

  日期：2007.12.1

  [GRAPHICS]Melanin-concentrating hormone (MCH) is implicated in the feeding behavior in mammals affording a potential target to control overeating in people. Compound 1 (AMG 076) has been identified as a potent MCHr1 antagonist for the treatment of obesity. A synthesis suitable for the large-scale preparation of this lead candidate was developed to support preclinical studies. A Robinson annulation of benzylpiperidone and resolution of the desired enone from a mixture of the diastereomers afforded key intermediate 6 after a stereoselective hydrogenation. Subsequent Fischer indole synthesis with hydrazine 5 then provided the advanced intermediate, indole 2. Two complementary reductive amination strategies employing either aldehyde 3 or lactol 4 led to the synthesis of title compound 1.
• Fused heterocyclic compounds
  申请人：Chen Xi

  公开号：US20080058365A1

  公开（公告）日：2008-03-06

  Compounds, compositions and methods are provided that are useful in the treatment and/or prevention of a condition or disorder mediated by a G-protein coupled receptor. In particular, the compounds of the invention are useful in the treatment and/or prevention of eating disorders, obesity, anxiety disorders and mood disorders.
• US7253179B2
  申请人：——

  公开号：US7253179B2

  公开（公告）日：2007-08-07