1-benzyl-2(5,5-dimethyl-1,3-dioxan-2-yl)-4,5-diphenylimidazole | 135098-38-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-benzyl-2(5,5-dimethyl-1,3-dioxan-2-yl)-4,5-diphenylimidazole
• 英文别名: 1-Benzyl-2-(5,5-dimethyl-1,3-dioxan-2-yl)-4,5-diphenylimidazole
• CAS: 135098-38-3
• 化学式: C₂₈H₂₈N₂O₂
• 分子量: 424.543
• InChiKey: BIHFNARCMHLDDD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.6
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  36.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-benzyl-2(5,5-dimethyl-1,3-dioxan-2-yl)-4,5-diphenylimidazole 在 氨 、 sodium 作用下， 以 四氢呋喃 为溶剂， 反应 0.67h， 生成 2-(5,5-dimethyl-1,3-dioxan-2-yl)-4,5-diphenylimidazole
  参考文献：
  名称：

  Acyl-CoA:Cholesterol O-Acyltransferase (ACAT) Inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as Potent Inhibitors of ACAT

  摘要：

  The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.

  DOI：

  10.1021/jm9505876
• 作为产物：
  描述：

  2,2-二甲基-1,3-丙二醇 、 1-benzyl-4,5-diphenylimidazole-2-carboxaldehyde 在 4-甲基苯磺酸吡啶 作用下， 以 甲苯 为溶剂， 反应 18.0h， 生成 1-benzyl-2(5,5-dimethyl-1,3-dioxan-2-yl)-4,5-diphenylimidazole
  参考文献：
  名称：

  Acyl-CoA:Cholesterol O-Acyltransferase (ACAT) Inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1H-imidazoles as Potent Inhibitors of ACAT

  摘要：

  The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.

  DOI：

  10.1021/jm9505876

文献信息

• Imidazoles
  申请人：RHONE-POULENC SANTE

  公开号：EP0424195A1

  公开（公告）日：1991-04-24

  Imidazole derivatives of the formula: wherein R¹ represents halogen, alkyl or alkoxy, n is 0 to 5, R² represents hydrogen or alkyl, R³ represents hydrogen or alkyl optionally substituted by halogen, hydroxy, acyloxy alkoxy, hydroxyalkoxy, acyloxyalkoxy, or by optionally substituted phenyl, or the groups R³ and the carbon atom to which they are attached together form a cycloalkane or cycloalkene group, are pharmaceutically useful as anti-­atherosclerotic agents.

  式中的咪唑衍生物： 其中 R¹ 代表卤素、烷基或烷氧基，n 为 0 至 5，R² 代表氢或烷基，R³ 代表氢或可选被卤素、羟基、酰氧基烷氧基、羟基烷氧基、酰氧基烷氧基或可选被取代的苯基取代的烷基，或基团 R³ 及其所连接的碳原子共同形成环烷或环烷烃基团。
• US5102900A
  申请人：——

  公开号：US5102900A

  公开（公告）日：1992-04-07
• Acyl-CoA:Cholesterol <i>O</i>-Acyltransferase (ACAT) Inhibitors. 2. 2-(1,3-Dioxan-2-yl)-4,5-diphenyl-1<i>H</i>-imidazoles as Potent Inhibitors of ACAT
  作者：Peter C. Astles、Michael J. Ashton、Andrew W. Bridge、Neil V. Harris、Terrance W. Hart、David P. Parrott、Barry Porter、David Riddell、Christopher Smith、Robert J. Williams

  DOI：10.1021/jm9505876

  日期：1996.1.1

  The second in this series of papers concerns our further investigations into the search for a potent bioavailable acyl-CoA:cholesterol O-acyltransferase (ACAT) inhibitor suitable for the treatment of atherosclerosis. The design, synthesis, and structure-activity relationship for a series of ACAT inhibitors based on the 2-(1,3-dioxan-2-yl)-4,5-diphenyl-1H-imidazole pharmacophore are described. Compounds such as 13a bearing simple alkyl or hydroxymethyl substituents at the 5-position of the 1,3-dioxane ring are potent bioavailable inhibitors of the rat hepatic microsomal enzyme in vitro (IC50 < 100 nM) but are only weak inhibitors of the human hepatic enzyme. We have found however that 1,3-dioxanes substituted at the 5-cis position with pyrazolylalkyl or aminoalkyl groups are potent inhibitors in vitro of human macrophage ACAT, the potency depending on the nature of the terminal heterocycle and the length of the alkyl chain. An ex vivo bioassay described herein demonstrates that potent inhibitors such as 13t (IC50 = 10 nM) which contain lipophilic terminal heterocycles do not appear to be systemically available. Less potent but more water soluble compounds such as 13h (IC50 = 60 nM) and 13n (IC50 = 70 nM) are absorbed following oral dosing and achieve plasma levels significantly in excess of their IC50 for ACAT inhibition. These compounds are therefore possible candidates for further investigation as oral antiatherosclerotic agents.