Formic acid (3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-formyloxy-17-((R)-3-isocyanato-1-methyl-propyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yl ester | 905915-45-9

• 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
• 英文名称: Formic acid (3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-formyloxy-17-((R)-3-isocyanato-1-methyl-propyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yl ester
• 英文别名: [(3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-formyloxy-17-[(2R)-4-isocyanatobutan-2-yl]-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
• CAS: 905915-45-9
• 化学式: C₂₆H₃₉NO₅
• 分子量: 445.599
• InChiKey: AGWAHRBIJGVZDJ-WLZWUTLSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  82
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Formic acid (3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-formyloxy-17-((R)-3-isocyanato-1-methyl-propyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yl ester 在 potassium carbonate 作用下， 以 甲醇 、 甲苯 为溶剂， 生成 23-N-(thiophene-2-methyloxycarbonyl)-3α,7α-dihydroxy-24-nor-5β-cholan-23-amine
  参考文献：
  名称：

  Back Door Modulation of the Farnesoid X Receptor:  Design, Synthesis, and Biological Evaluation of a Series of Side Chain Modified Chenodeoxycholic Acid Derivatives

  摘要：

  Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the carboxylic tail opposite the transactivation function 2 (AF-2, helix 12), functionalization of the side chain is not expected to interfere directly with the orientation of H12 but can result in a more indirect way of receptor modulation. The newly synthesized compounds were extensively characterized for their ability to modulate FXR function in a variety of assays, including the cell-free fluorescence resonance energy transfer (FRET) assay and the cell-based luciferase transactivation assay, and displayed a broad range of activity from full agonism to partial antagonism. Docking studies clearly indicate that the side chain of the new derivatives fits in a so far unexploited receptor cavity localized near the "back door" of FXR. We thus demonstrate the possibility of achieving a broad FXR modulation without directly affecting the H12 orientation.

  DOI：

  10.1021/jm060294k
• 作为产物：
  描述：

  3α,7α-diformyloxy-5β-cholan-24-oic acid 在 sodium azide 、 草酰氯 作用下， 以 丙酮 、 甲苯 为溶剂， 反应 11.0h， 生成 Formic acid (3R,5S,7R,8R,9S,10S,13R,14S,17R)-7-formyloxy-17-((R)-3-isocyanato-1-methyl-propyl)-10,13-dimethyl-hexadecahydro-cyclopenta[a]phenanthren-3-yl ester
  参考文献：
  名称：

  Back Door Modulation of the Farnesoid X Receptor:  Design, Synthesis, and Biological Evaluation of a Series of Side Chain Modified Chenodeoxycholic Acid Derivatives

  摘要：

  Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the carboxylic tail opposite the transactivation function 2 (AF-2, helix 12), functionalization of the side chain is not expected to interfere directly with the orientation of H12 but can result in a more indirect way of receptor modulation. The newly synthesized compounds were extensively characterized for their ability to modulate FXR function in a variety of assays, including the cell-free fluorescence resonance energy transfer (FRET) assay and the cell-based luciferase transactivation assay, and displayed a broad range of activity from full agonism to partial antagonism. Docking studies clearly indicate that the side chain of the new derivatives fits in a so far unexploited receptor cavity localized near the "back door" of FXR. We thus demonstrate the possibility of achieving a broad FXR modulation without directly affecting the H12 orientation.

  DOI：

  10.1021/jm060294k

文献信息

• BILE ACID DERIVATIVES AS FXR LIGANDS FOR THE PREVENTION OR TREATMENT OF FXR-MEDIATED DISEASES OR CONDITIONS
  申请人：Pellicciari Roberto

  公开号：US20100063018A1

  公开（公告）日：2010-03-11

  The present invention relates to compounds of formula (I) wherein: R 1 is hydrogen or an alkyl group; R 2 is hydrogen or a halogen, nitro, alkyloxy, amino or carboxy group; Y is CH 2 , oxygen or sulfur; n is an integer from 1 to 4, and pharmaceutically acceptable salts, solvates or amino acid conjugates thereof for the treatment of FXR-mediated diseases or conditions.

  本发明涉及具有以下结构的化合物（I）：其中：R1是氢或烷基基团；R2是氢或卤素、硝基、烷氧基、氨基或羧基团；Y是CH2、氧或硫；n是1到4的整数，以及其在治疗FXR介导的疾病或症状中的药用盐、溶剂化合物或氨基酸结合物。
• Back Door Modulation of the Farnesoid X Receptor:  Design, Synthesis, and Biological Evaluation of a Series of Side Chain Modified Chenodeoxycholic Acid Derivatives
  作者：Roberto Pellicciari、Antimo Gioiello、Gabriele Costantino、Bahman M. Sadeghpour、Giovanni Rizzo、Udo Meyer、Derek J. Parks、Antonio Entrena-Guadix、Stefano Fiorucci

  DOI：10.1021/jm060294k

  日期：2006.7.1

  Carbamate derivatives of bile acids were synthesized with the aim of systematically exploring the potential for farnesoid X receptor (FXR) modulation endowed with occupancy of the receptor's back door, localized between loops H1-H2 and H4-H5. Since it was previously shown that bile acids bind to FXR by projecting the carboxylic tail opposite the transactivation function 2 (AF-2, helix 12), functionalization of the side chain is not expected to interfere directly with the orientation of H12 but can result in a more indirect way of receptor modulation. The newly synthesized compounds were extensively characterized for their ability to modulate FXR function in a variety of assays, including the cell-free fluorescence resonance energy transfer (FRET) assay and the cell-based luciferase transactivation assay, and displayed a broad range of activity from full agonism to partial antagonism. Docking studies clearly indicate that the side chain of the new derivatives fits in a so far unexploited receptor cavity localized near the "back door" of FXR. We thus demonstrate the possibility of achieving a broad FXR modulation without directly affecting the H12 orientation.