anti-(±)-3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: anti-(±)-3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one
• 英文别名: 4-(4-phenoxyphenyl)-3,6-dimethyl-1-(2-methylphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one；(4R,6R)-3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydropyrazolo[3,4-e][1,4]thiazepin-7-one
• 化学式: C₂₇H₂₅N₃O₂S
• 分子量: 455.58
• InChiKey: MPYMLMWPLLVIIO-KBMIEXCESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  81.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  (2-甲基苯基)肼 在 盐酸 作用下， 以 水 、 甲苯 为溶剂， 反应 12.0h， 生成 syn-(±)-3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one 、 anti-(±)-3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one
  参考文献：
  名称：

  新型非甾体类法尼醇X受体（FXR）激动剂的四个非对映异构体的不对称合成：手性对生物活性的作用

  摘要：

  设计了一种不对称合成策略，用于制备3,6-二甲基-1-（2-甲基苯基）-4-（4-苯氧基苯基）-4,8-​​二氢-1H-吡唑并[ 4]的四种可能的非对映异构体。我们最近通过虚拟筛选方法发现了4- e ] [1,4] thiazepin-7-one（一种非甾体FXR激动剂）。从AlphaScreen分析获得的结果清楚地表明，只有具有4 R，6 S绝对构型的异构体才是生物活性的原因。使用计算模型研究对这些对映体纯配体采用的不同推定结合模式进行了深入研究，证实了FXR对此类分子的对映选择性。

  DOI：

  10.1016/j.bmc.2013.04.038

文献信息

• Pyrazole[3,4-e][1,4]thiazepin-7-one derivatives as a novel class of Farnesoid X Receptor (FXR) agonists
  作者：Maura Marinozzi、Andrea Carotti、Emanuele Sansone、Antonio Macchiarulo、Emiliano Rosatelli、Roccaldo Sardella、Benedetto Natalini、Giovanni Rizzo、Luciano Adorini、Daniela Passeri、Francesca De Franco、Mark Pruzanski、Roberto Pellicciari

  DOI：10.1016/j.bmc.2012.04.021

  日期：2012.6

  A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20 mu M. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7-one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy. (C) 2012 Elsevier Ltd. All rights reserved.
• Asymmetric synthesis of the four diastereoisomers of a novel non-steroidal farnesoid X receptor (FXR) agonist: Role of the chirality on the biological activity
  作者：Maura Marinozzi、Andrea Carotti、Roccaldo Sardella、Federica Buonerba、Federica Ianni、Benedetto Natalini、Daniela Passeri、Giovanni Rizzo、Roberto Pellicciari

  DOI：10.1016/j.bmc.2013.04.038

  日期：2013.7

  designed for the preparation of the four possible diastereoisomers of 3,6-dimethyl-1-(2-methylphenyl)-4-(4-phenoxyphenyl)-4,8-dihydro-1H-pyrazolo[3,4-e][1,4]thiazepin-7-one, a non-steroidal FXR agonist, we recently discovered following a virtual screening approach. The results obtained from an AlphaScreen assay clearly demonstrated that only the isomer endowed with 4R,6S absolute configuration is responsible

  设计了一种不对称合成策略，用于制备3,6-二甲基-1-（2-甲基苯基）-4-（4-苯氧基苯基）-4,8-​​二氢-1H-吡唑并[ 4]的四种可能的非对映异构体。我们最近通过虚拟筛选方法发现了4- e ] [1,4] thiazepin-7-one（一种非甾体FXR激动剂）。从AlphaScreen分析获得的结果清楚地表明，只有具有4 R，6 S绝对构型的异构体才是生物活性的原因。使用计算模型研究对这些对映体纯配体采用的不同推定结合模式进行了深入研究，证实了FXR对此类分子的对映选择性。