25,26-bis-homo-3α,7α-dihydroxy-5β-cholan-26-oic acid | 71743-91-4

• 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: 25,26-bis-homo-3α,7α-dihydroxy-5β-cholan-26-oic acid
• 英文别名: 3α,7α-dihydroxy-27-nor-5β-cholestan-26-oic acid；Dihomochenodeoxycholic acid；(6R)-6-[(3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-17-yl]heptanoic acid
• CAS: 71743-91-4
• 化学式: C₂₆H₄₄O₄
• 分子量: 420.633
• InChiKey: ISELACRIJKHUTE-BJLOMENOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.96
• 拓扑面积：
  77.8
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  25,26-bis-homo-3α,7α-dihydroxy-5β-cholan-26-oic acid 在 lithium aluminium tetrahydride 作用下， 生成 25,26-bis-homo-3α,7α,26-5β-cholantriol
  参考文献：
  名称：

  Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor

  摘要：

  TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. In the present study, we evaluated the ability of bile alcohols, which are structurally and physiologically similar to bile acids and are produced as the end products of cholesterol catabolism in evolutionarily primitive vertebrates, to act as TGR5 agonists. In a cell-based reporter assay and a cAMP production assay performed in vitro, most bile alcohols with a side chain containing hydroxyl group(s) were highly efficacious agonists for TGR5 comparable to its most potent ligand in the naturally occurring bile acid, lithocholic acid. However, the abilities of the bile alcohols to activate TGR5 varied with the position and number of the hydroxyl substituent in the side chain. Additionally, the conformation of the steroidal nucleus of bile alcohols is also important for its activity as a TGR5 agonist. Thus, we have provided new insights into the structure-activity relationships of bile alcohols as TGR5 agonists.-Iguchi, Y., M. Yamaguchi, H. Sato, K. Kihira, T. Nishimaki-Mogami, and M. Une. Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor. J. Lipid Res. 2010. 51: 1432-1441.

  DOI：

  10.1194/jlr.m004051
• 作为产物：
  描述：

  methyl (R)-4-((3R,5S,7R,8R,9S,10S,13R,14S,17R)-3,7-bis((tert-butyldimethylsilyl)oxy)-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthren-17-yl)pentanoate 在 锂硼氢 、 草酰氯 、 二甲基亚砜 、 sodium hydroxide 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 5.5h， 生成 25,26-bis-homo-3α,7α-dihydroxy-5β-cholan-26-oic acid
  参考文献：
  名称：

  Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)

  摘要：

  Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3 alpha,7 beta-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of proglucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.

  DOI：

  10.1021/jm500889f

文献信息

• Modification on Ursodeoxycholic Acid (UDCA) Scaffold. Discovery of Bile Acid Derivatives As Selective Agonists of Cell-Surface G-Protein Coupled Bile Acid Receptor 1 (GP-BAR1)
  作者：Valentina Sepe、Barbara Renga、Carmen Festa、Claudio D’Amore、Dario Masullo、Sabrina Cipriani、Francesco Saverio Di Leva、Maria Chiara Monti、Ettore Novellino、Vittorio Limongelli、Angela Zampella、Stefano Fiorucci

  DOI：10.1021/jm500889f

  日期：2014.9.25

  Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3 alpha,7 beta-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of proglucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1.
• Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor
  作者：Yusuke Iguchi、Masafumi Yamaguchi、Hiroyuki Sato、Kenji Kihira、Tomoko Nishimaki-Mogami、Mizuho Une

  DOI：10.1194/jlr.m004051

  日期：2010.6

  TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. In the present study, we evaluated the ability of bile alcohols, which are structurally and physiologically similar to bile acids and are produced as the end products of cholesterol catabolism in evolutionarily primitive vertebrates, to act as TGR5 agonists. In a cell-based reporter assay and a cAMP production assay performed in vitro, most bile alcohols with a side chain containing hydroxyl group(s) were highly efficacious agonists for TGR5 comparable to its most potent ligand in the naturally occurring bile acid, lithocholic acid. However, the abilities of the bile alcohols to activate TGR5 varied with the position and number of the hydroxyl substituent in the side chain. Additionally, the conformation of the steroidal nucleus of bile alcohols is also important for its activity as a TGR5 agonist. Thus, we have provided new insights into the structure-activity relationships of bile alcohols as TGR5 agonists.-Iguchi, Y., M. Yamaguchi, H. Sato, K. Kihira, T. Nishimaki-Mogami, and M. Une. Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor. J. Lipid Res. 2010. 51: 1432-1441.