7-羟基-4-胆甾烯-3-酮 | 3862-25-7

• 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
• 中文名称: 7-羟基-4-胆甾烯-3-酮
• 中文别名: 7Α-羟基-4-胆固醇-3-酮
• 英文名称: Δ⁴-7α-hydrocholesterol
• 英文别名: 7α-hydroxycholest-4-ene-3-one；7-α-hydroxycholest-4-en-3-one；7α-hydroxy-4-cholesten-3-one；7α-hydroxycholest-4-en-3-one；7α-Hydroxy-cholest-4-en-3-on；7α-Hydroxy-4-cholesten-3-on；7alpha-Hydroxy-4-cholesten-3-one；(7R,8S,9S,10R,13R,14S,17R)-7-hydroxy-10,13-dimethyl-17-[(2R)-6-methylheptan-2-yl]-1,2,6,7,8,9,11,12,14,15,16,17-dodecahydrocyclopenta[a]phenanthren-3-one
• CAS: 3862-25-7
• 化学式: C₂₇H₄₄O₂
• mdl: MFCD00870345
• 分子量: 400.645
• InChiKey: IOIZWEJGGCZDOL-RQDYSCIWSA-N

物化性质

• 熔点：
  182-184°C
• 沸点：
  516.7±29.0 °C(Predicted)
• 密度：
  1.03±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.888
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  2

安全信息

• WGK Germany：
  3
• 储存条件：
  -20°C

制备方法与用途

生物活性

7α-羟基-4-胆固醇-3-酮（7α-Hydroxy-4-cholesten-3-one）是一种由胆固醇合成胆汁酸的中间体，同时也是孕烷 X 受体 (PXR) 激动剂。此外，它还是胆汁酸流失、肠易激综合征及其他与胆汁酸生物合成缺陷有关疾病的生物标志物。7α-羟基-4-胆固醇-3-酮也是一种 CYP8B1 的生理底物。

靶点

内源性代谢物：孕烷 X 受体 (PXR)

体外研究

7α-羟基-4-胆固醇-3-酮在胆汁酸（如熊去氧胆酸）生物合成路径中相对靠前的位置被发现。首先，细胞色素 P450 7A1 将 7α 羟基附着到胆固醇上；其次，在 3β-羟基固醇脱氢酶的作用下进行氧化和异构化反应生成 7α-羟基-4-胆固醇-3-酮。当下游胆汁酸途径中表达 P450 27A1 的基因被删除时，会导致前体物质 7α-羟基-4-胆固醇-3-酮的积累。

体内研究

在稳态条件下及大鼠快速昼夜变化期间，7α-羟基-4-胆固醇-3-酮与肝细胞中 CYP7A1 的酶活性密切相关。其血清浓度具有显著的日间节律性。

反应信息

• 作为反应物：
  描述：

  7-羟基-4-胆甾烯-3-酮 在 cytochrome P₄₅₀ 8B₁ 作用下， 生成 7,12-二羟基-4-胆甾烯-3-酮
  参考文献：
  名称：

  Additional pathways of sterol metabolism: Evidence from analysis of Cyp27a1−/− mouse brain and plasma

  摘要：

  Cytochrome P450 (CYP) 27A1 is a key enzyme in both the acidic and neutral pathways of bile acid biosynthesis accepting cholesterol and ring-hydroxylated sterols as substrates introducing a (25R) 26-hydroxy and ultimately a (25R) 26-acid group to the sterol side-chain. In human, mutations in the CYP27A1 gene are the cause of the autosomal recessive disease cerebrotendinous xanthomatosis (CTX). Surprisingly, Cyp27a1 knockout mice (Cyp27a1-/-) do not present a CTX phenotype despite generating a similar global pattern of sterols. Using liquid chromatography - mass spectrometry and exploiting a charge-tagging approach for oxysterol analysis we identified over 50 cholesterol metabolites and precursors in the brain and circulation of Cyp27a1-/- mice. Notably, we identified (25R) 26,7 alpha- and (25S) 26,7 alpha-dihydroxy epimers of oxysterols and cholestenoic acids, indicating the presence of an additional sterol 26-hydroxylase in mouse. Importantly, our analysis also revealed elevated levels of 7 alpha-hydroxycholest-4-en-3-one, which we found increased the number of oculomotor neurons in primary mouse brain cultures. 7 alpha-Hydroxycholest-4-en-3-one is a ligand for the pregnane X receptor (PXR), activation of which is known to up-regulate the expression of CYP3A11, which we confirm has sterol 26-hydroxylase activity. This can explain the formation of (25R) 26,7 alpha- and (25S) 26,7 alpha-dihydroxy epimers of oxysterols and cholestenoic acids; the acid with the former stereochemistry is a liver X receptor (LXR) ligand that increases the number of oculomotor neurons in primary brain cultures. We hereby suggest that a lack of a motor neuron phenotype in some CTX patients and Cyp27a1-/- mice may involve increased levels of 7 alpha-hydroxycholest-4-en-3-one and activation PXR, as well as increased levels of sterol 26-hydroxylase and the production of neuroprotective sterols capable of activating LXR.

  DOI：

  10.1016/j.bbalip.2018.11.006
• 作为产物：
  描述：

  4-胆甾烯-3-酮 在 tris-(dibenzylideneacetone)dipalladium(0) 、 甲酸 、 四氯苯醌 、 对甲苯磺酸 、 三乙胺 、 间氯过氧苯甲酸 、 三苯基膦 作用下， 以 四氢呋喃 、 氯仿 、 甲苯 、 叔丁醇 为溶剂， 反应 37.0h， 生成 7-羟基-4-胆甾烯-3-酮
  参考文献：
  名称：

  [EN] COMPETITIVE IMMUNOASSAY METHODS
  [FR] PROCÉDÉS DE DOSAGE IMMUNOLOGIQUE PAR COMPÉTITION

  摘要：

  本发明提供了检测、测量或定量生物样本中7α-羟基-4-胆甾烯-3-酮（7C4）水平的测定方法和试剂盒，所述生物样本来自于受试者，例如人类受试者。在某些实施方式中，人类受试者患有与胆酸吸收不良或不明原因腹泻相关的疾病。本发明还提供了特异性结合于7α-羟基-4-胆甾烯-3-酮（7C4）并且与7-酮胆固醇、7α-羟基胆固醇和三羟基胆甾酸中的一个或多个成员的交叉反应小于1％的分离抗体或抗体片段。

  公开号：

  WO2018011691A1

文献信息

• Bile Acid Recycling Inhibitors for Treatment of Hypercholemia and Cholestatic Liver Disease
  申请人：Lumena Pharmaceuticals, Inc.

  公开号：US20130108573A1

  公开（公告）日：2013-05-02

  Provided herein are methods of treating or ameliorating hypercholemia or a cholestatic liver disease by administering to an individual in need thereof a therapeutically effective amount of an Apical Sodium-dependent Bile Acid Transporter Inhibitor (ASBTI) or a pharmaceutically acceptable salt thereof. Also provided are methods for treating or ameliorating a liver disease, decreasing the levels of serum bile acids or hepatic bile acids, treating or ameliorating pruritis, reducing liver enzymes, or reducing bilirubin comprising administering to an individual in need thereof a therapeutically effective amount of ASBTI or a pharmaceutically acceptable salt thereof.

  本文提供了一种治疗或改善高胆固醇血症或胆汁淤积性肝病的方法，即通过向需要的个体施用治疗有效量的顶端钠依赖性胆酸转运蛋白抑制剂（ASBTI）或其药用可接受盐。还提供了一种治疗或改善肝病、降低血清胆酸或肝内胆酸水平、治疗或改善瘙痒、降低肝酶或减少胆红素的方法，即通过向需要的个体施用治疗有效量的ASBTI或其药用可接受盐。
• Chemical synthesis of 7α-hydroxycholest-4-en-3-one, a biomarker for irritable bowel syndrome and bile acid malabsorption
  作者：Samuel D. Offei、Hadi D. Arman、Francis K. Yoshimoto

  DOI：10.1016/j.steroids.2019.108449

  日期：2019.11

  syndrome, and other diseases associated with defective bile acid biosynthesis. Furthermore, 7α-hydroxy-cholest-4-en-3-one is the physiological substrate for cytochrome P450 8B1 (P450 8B1 or CYP8B1), the oxysterol 12α-hydroxylase enzyme implicated in obesity and cardiovascular health. We report the chemical synthesis of this physiologically important oxysterol beginning with cholesterol. The key feature

  7α-Hydroxy-cholest-4-en-3-one是胆汁酸流失，肠易激综合征和其他与胆汁酸生物合成缺陷有关的疾病的生物标志物。此外，7α-羟基胆甾醇4-en-3-one是细胞色素P450 8B1（P450 8B1或CYP8B1）的生理底物，P450 8B1或CYP8B1是与肥胖症和心血管健康有关的氧固醇12α-羟化酶。我们从胆固醇开始报告了这种具有重要生理意义的氧固醇的化学合成。该合成的关键特征涉及3-脱氧-Δ4-7α-甲酸酯类固醇前体的区域选择性C3-烯丙基氧化形成7α-甲氧基-胆甾醇4-en-3-one，将其皂化生成7α-羟基-cholest-4-en-3-one。
• FUNCTIONALIZED LONG-CHAIN HYDROCARBON MONO- AND DI-CARBOXYLIC ACIDS AND THEIR USE FOR THE PREVENTION OR TREATMENT OF DISEASE
  申请人：ESPERVITA THERAPEUTICS, INC.

  公开号：US20210024447A1

  公开（公告）日：2021-01-28

  This invention provides compounds of Formulae (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), (IL), (II), (III), (IIIA), and (IIIB); pharmaceutically acceptable salts and solvates thereof; and compositions thereof. This invention further provides methods for treating a disease, including but not limited to, liver disease or an abnormal liver condition; cancer (such as hepatocellular carcinoma or cholangiocarcinoma); a malignant or benign tumor of the lung, liver, gall bladder, bile duct or digestive tract; an intra- or extra-hepatic bile duct disease; a disorder of lipoprotein; a lipid-and-metabolic disorder; cirrhosis; fibrosis; a disorder of glucose metabolism; a cardiovascular or related vascular disorder; a disease resulting from steatosis, fibrosis, or cirrhosis; a disease associated with increased inflammation (such as hepatic inflammation or pulmonary inflammation); hepatocyte ballooning; a peroxisome proliferator activated receptor-associated disorder; an ATP citrate lyase disorder; an acetyl-coenzyme A carboxylase disorder; obesity; pancreatitis; or renal disease.

  这项发明提供了Formulae（IA）、（IB）、（IC）、（ID）、（IE）、（IF）、（IG）、（IH）、（IJ）、（IK）、（IL）、（II）、（III）、（IIIA）和（IIIB）的化合物；这些化合物的药学上可接受的盐和溶剂；以及它们的组合物。这项发明还提供了治疗疾病的方法，包括但不限于肝病或异常肝脏状况；癌症（如肝细胞癌或胆管癌）；肺、肝、胆囊、胆管或消化道的恶性或良性肿瘤；肝内或肝外胆管疾病；脂蛋白紊乱；脂质和代谢紊乱；肝硬化；纤维化；葡萄糖代谢紊乱；心血管或相关血管紊乱；由脂肪变性、纤维化或肝硬化引起的疾病；与炎症增加有关的疾病（如肝炎或肺炎炎症）；肝细胞球形变；过氧化物酶体增殖子激活受体相关的疾病；ATP柠檬酸裂合酶疾病；乙酰辅酶A羧化酶疾病；肥胖；胰腺炎；或肾脏疾病。
• [EN] SYNTHETIC METHODS<br/>[FR] MÉTHODES SYNTHÉTIQUES
  申请人：GLAXOSMITHKLINE INTELLECTUAL PROPERTY (NO 2) LTD

  公开号：WO2018002827A1

  公开（公告）日：2018-01-04

  Methods for the preparation of the following compound are disclosed. The compound can be incorporated into pharmaceutical formulations, including tablets and such tablets can be used for treating cholestatic liver diseases.

  揭示了制备以下化合物的方法。该化合物可以用于制备药物配方，包括片剂，这些片剂可用于治疗胆汁淤积性肝病。
• Novel quaternary ammonium compounds
  申请人：Sasahara Takehiko

  公开号：US20050009805A1

  公开（公告）日：2005-01-13

  [Object] To provide a medicine useful for treatment and prevention of hyperlipidemia, further for the treatment and prevention of cholestasis-accompanying hepatopathy, particularly primary biliary cirrhosis and primary sclerosing cholangitis, and for the treatment and prevention of obesity and fatty liver. [Means] A benzothiazepine compound represented by the following formula (1), having a thioamide bond and a quaternary ammonium substituent.

  提供一种用于治疗和预防高脂血症，尤其是原发性胆汁性肝病，特别是原发性胆汁性肝硬化和原发性硬化性胆管炎，以及治疗和预防肥胖和脂肪肝的药物。代表如下式（1）的苯并噻二唑化合物，具有硫酰胺键和季铵基取代基。