(4R)-4-((3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-bis(formyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid | 1301212-63-4

• 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
• 英文名称: (4R)-4-((3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-bis(formyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid
• 英文别名: 3α,7α-diformyloxy-6α-ethyl-5β-cholan-24-oic acid；3α,7α-diformyl CDCA；(4R)-4-[(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-diformyloxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid
• CAS: 1301212-63-4
• 化学式: C₂₈H₄₄O₆
• 分子量: 476.654
• InChiKey: RGHDRPNHXMGIQL-NQGMLVFVSA-N

物化性质

• 沸点：
  572.5±29.0 °C(Predicted)
• 密度：
  1.13±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  89.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4R)-4-((3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-bis(formyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid 在 吡啶 、 碘苯二乙酸 、 copper diacetate 作用下， 以 甲苯 为溶剂， 反应 12.0h， 生成 [(3R,5S,6R,7R,8S,9S,10S,13R,14S,17R)-17-[(2R)-but-3-en-2-yl]-6-ethyl-7-formyloxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl] formate
  参考文献：
  名称：

  胆酸衍生物及其制备方法和用途

  摘要：

  本发明公开了一种胆酸衍生物及其制备方法和用途。本发明的胆酸衍生物结构如式I所示，其中，各取代基的定义如说明书和权利要求书中所述。本发明的胆酸衍生物具有FXR激动活性高、合成简单、原料易得等优点。

  公开号：

  CN109134572A
• 作为产物：
  描述：

  (E/Z)-3α-hydroxy-6-ethylidene-7-keto-5β-cholan-24-oic acid 在 sodium tetrahydroborate 、 高氯酸 、 palladium 10% on activated carbon 、 水 、 氢气 、 sodium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 55.0~100.0 ℃ 、103.42 kPa 条件下， 反应 24.0h， 生成 (4R)-4-((3R,6R,7R,8S,9S,10S,13R,14S,17R)-6-ethyl-3,7-bis(formyloxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid
  参考文献：
  名称：

  EP3409684

  摘要：

  公开号：

文献信息

• Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH
  作者：Hualing Xiao、Peng Li、Xiaolin Li、Haiying He、Jianhua Wang、Fengxun Guo、Jiliang Zhang、Luxia Wei、Hongmei Zhang、Yueyuan Shi、Lijuan Hou、Liang Shen、Zhengxia Chen、Chunyan Du、Shouliang Fu、Pengtao Zhang、Fei Hao、Ping Wang、Deming Xu、Wei Liang、Xin Tian、Aiming Zhang、Xingdong Cheng、Ling Yang、Xiangjian Wang、Xiquan Zhang、Jian Li、Shuhui Chen

  DOI：10.1021/acsmedchemlett.7b00318

  日期：2017.12.14

  to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic

  Farnesoid X受体（FXR）已成为发现用于治疗肝脏和代谢性疾病的药物的特别有吸引力的靶标。FXR激动剂奥贝胆酸（INT-747）已进入非酒精性脂肪性肝炎（NASH）患者的III期临床试验，但观察到不良反应（例如瘙痒，LDL升高）。武田G蛋白偶联受体5（TGR5，GPBAR1）可能引起瘙痒，并且有机会开发出比TGR5具有更高选择性的FXR激动剂。在这封信中，报道并讨论了在INT-747的A环和侧链上进行不同修饰的新型胆汁酸。我们的结果表明INT-747的侧链在体外具有良好的FXR效力，可进行多种化学修饰。特别地，化合物18不仅显示出有希望的FXR效力和优异的药代动力学性质，而且在HFD + CCl 4模型中证明了优异的药理学功效。
• THERAPEUTIC COMPOUNDS AND METHODS OF USE THEREOF
  申请人：REGENTS OF THE UNIVERSITY OF MINNESOTA

  公开号：US20200376007A1

  公开（公告）日：2020-12-03

  The invention provides a compound of formula (I): or a salt thereof, wherein R 1 , R 2 , R 3 , R 4 and R 6 have any of the values described in the specification, as well as compositions comprising a compound of formula (I). The compounds are agonists of the TGR5 receptor.

  该发明提供了一个化合物的结构式(I)：或其盐，其中R1、R2、R3、R4和R6可以取得规范中描述的任何值，以及包含结构式(I)化合物的组合物。这些化合物是TGR5受体的激动剂。
• Extending SAR of bile acids as FXR ligands: Discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine
  作者：Antimo Gioiello、Antonio Macchiarulo、Andrea Carotti、Paolo Filipponi、Gabriele Costantino、Giovanni Rizzo、Luciano Adorini、Roberto Pellicciari

  DOI：10.1016/j.bmc.2011.03.004

  日期：2011.4

  Within our efforts in the discovery of novel potent and selective ligands for the FXR receptor, 23-N-(carbocinnamyloxy)-3 alpha,7 alpha-dihydroxy-6 alpha-ethyl-24-nor-5 beta-cholan-23-amine was synthesized and evaluated for its ability to activate and modulate the biological response of the receptor. Alphascreen and RT-PCR revealed that the 6 alpha-ethyl-24-norcholanyl-23-amine derivate behaves as full FXR agonist endowed with high binding affinity and efficacy, representing a promising lead candidate for further optimization. In addition, docking studies provide new insights into the molecular basis governing the partial and full agonist activity at FXR. (C) 2011 Elsevier Ltd. All rights reserved.
• Bile Acid Derivatives as FXR/TGR5 Agonists and Methods of Use Thereof
  申请人：Enanta Pharmaceuticals, Inc.

  公开号：US20160176917A1

  公开（公告）日：2016-06-23

  The present invention provides compounds of Formula I, pharmaceutical compositions comprising these compounds and methods of using these compounds to prevent or treat FXR-mediated or TGR5-mediated diseases or conditions.
• BILE ACID DERIVATIVES AS FXR/TGR5 AGONISTS AND METHODS OF USE THEREOF
  申请人：Enanta Pharmaceuticals, Inc.

  公开号：US20160185815A1

  公开（公告）日：2016-06-30

  The present invention provides compounds of Formula I, pharmaceutical compositions comprising these compounds and methods of using these compounds to prevent or treat FXR-mediated or TGR5-mediated diseases or conditions.