| 1612192-30-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• CAS: 1612192-30-9
• 化学式: C₄₀H₇₆O₄Si₂
• 分子量: 677.212
• InChiKey: YOPPLKMRSWSUFA-RTMPEPGZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  11.8
• 重原子数：
  46.0
• 可旋转键数：
  11.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.97
• 拓扑面积：
  44.76
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 5.0h， 以81%的产率得到ethyl 25,26-bis-homo-3α,7α-dihydroxy-5β-cholan-26-oate
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors

  摘要：

  Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.

  DOI：

  10.1021/jm401873d
• 作为产物：
  描述：

  鹅去氧胆酸 在 2,6-二甲基吡啶 、 甲醇 、 锂硼氢 、 草酰氯 、 palladium hydroxide, 20 wt% on carbon 、 氢气 、 对甲苯磺酸 、 二甲基亚砜 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， -78.0~20.0 ℃ 、344.75 kPa 条件下， 反应 10.75h， 生成
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Potent Dual Agonists of Nuclear and Membrane Bile Acid Receptors

  摘要：

  Bile acids exert genomic and nongenomic effects by interacting with membrane G-protein-coupled receptors, including the bile acid receptor GP-BAR1, and nuclear receptors, such as the farnesoid X receptor (FXR). These receptors regulate overlapping metabolic functions; thus, GP-BAR1/FXR dual agonists, by enhancing the biological response, represent an innovative strategy for the treatment of enteroendocrine disorders. Here, we report the design, total synthesis, and in vitro/in vivo pharmacological evaluation of a new generation of dual bile acid receptor agonists, with the most potent compound, 19, showing promising pharmacological profiles. We show that compound 19 activates GP-BAR1, FXR, and FXR regulated genes in the liver, increases the intracellular concentration of cAMP, and stimulates the release of the potent insulinotropic hormone GLP-1, resulting in a promising drug candidate for the treatment of metabolic disorders. We also elucidate the binding mode of the most potent dual agonists in the two receptors through a series of computations providing the molecular basis for dual GP-BAR1/FXR agonism.

  DOI：

  10.1021/jm401873d