ethyl cis-4-({5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-2,3'-bipyridin-6'-yl}oxy)cyclohexanecarboxylate | 1442646-28-7

• 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: ethyl cis-4-({5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-2,3'-bipyridin-6'-yl}oxy)cyclohexanecarboxylate
• CAS: 1442646-28-7
• 化学式: C₂₇H₂₅F₃N₄O₃
• 分子量: 510.516
• InChiKey: UOSRCLIQGZFWEO-MOBUCQHHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.21
• 重原子数：
  37.0
• 可旋转键数：
  6.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  89.99
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  ethyl cis-4-({5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-2,3'-bipyridin-6'-yl}oxy)cyclohexanecarboxylate 在 lithium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以79%的产率得到(1s,4s)-4-((5-(5-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)-[2,3'-bipyridin]-6'-yl)oxy)cyclohexane-1-carboxylic acid
  参考文献：
  名称：

  Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

  摘要：

  We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.

  DOI：

  10.1021/ml400168h
• 作为产物：
  描述：

  2-溴-5-醛基吡啶 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium peroxymonosulfate 、 sodium carbonate 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl cis-4-({5-[5-(trifluoromethyl)-1H-benzimidazol-2-yl]-2,3'-bipyridin-6'-yl}oxy)cyclohexanecarboxylate
  参考文献：
  名称：

  Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety

  摘要：

  We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.

  DOI：

  10.1021/ml400168h

文献信息

• Potent DGAT1 Inhibitors in the Benzimidazole Class with a Pyridyl-oxy-cyclohexanecarboxylic Acid Moiety
  作者：Shuwen He、Qingmei Hong、Zhong Lai、Zhicai Wu、Yang Yu、David W. Kim、Pauline C. Ting、Jeffrey T. Kuethe、Ginger X. Yang、Tianying Jian、Jian Liu、Deodial Guiadeen、Arto D. Krikorian、Donald M. Sperbeck、Lisa M. Sonatore、Judyann Wiltsie、Christine C. Chung、Jack T. Gibson、JeanMarie Lisnock、Beth A. Murphy、Judith N. Gorski、Jinqi Liu、Dunlu Chen、Xiaoli Chen、Michael Wolff、Sharon X. Tong、Maria Madeira、Bindhu V. Karanam、Dong-Ming Shen、James M. Balkovec、Shirly Pinto、Ravi P. Nargund、Robert J. DeVita

  DOI：10.1021/ml400168h

  日期：2013.8.8

  We report the design and synthesis of a series of novel DGAT1 inhibitors in the benzimidazole class with a pyridyl-oxy-cyclohexanecarboxylic acid moiety. In particular, compound 11A is a potent DGAT1 inhibitor with excellent selectivity against ACAT1. Compound 11A significantly reduces triglyceride excursion in lipid tolerance tests (LTT) in both mice and dogs at low plasma exposure. An in vivo study in mice with des-fluoro analogue 10A indicates that this series of compounds appears to distribute in intestine preferentially over plasma. The propensity to target intestine over plasma could be advantageous in reducing potential side effects since lower circulating levels of drug are required for efficacy. However, in the preclinical species, compound 11A undergoes cis/trans epimerization in vivo, which could complicate further development due to the presence of an active metabolite.