methyl (4R)-4-[(8S,9S,10R,13R,14S,17R)-2-bromo-4,4,10,13-tetramethyl-3-oxo-2,7,8,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate | 1414953-72-2

• 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: methyl (4R)-4-[(8S,9S,10R,13R,14S,17R)-2-bromo-4,4,10,13-tetramethyl-3-oxo-2,7,8,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate
• CAS: 1414953-72-2
• 化学式: C₂₇H₄₁BrO₃
• 分子量: 493.525
• InChiKey: KENLEJVUPQQJIP-LRRZYKOESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  43.4
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  methyl (4R)-4-[(8S,9S,10R,13R,14S,17R)-2-bromo-4,4,10,13-tetramethyl-3-oxo-2,7,8,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate 在 水 、 lithium hydroxide 作用下， 以 乙醇 为溶剂， 生成 (4R)-4-[(1S,2R,13S,14S,17R,18R)-6-amino-2,9,9,18-tetramethyl-5-thia-7-azapentacyclo[11.7.0.02,10.04,8.014,18]icosa-4(8),6,10-trien-17-yl]pentanoic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC50 = 12.74 mu M) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.040
• 作为产物：
  描述：

  choladiene-1,4 one-3 oate-24 de methyle 在 potassium tert-butylate 、 benzyltrimethylazanium tribroman-2-uide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 methyl (4R)-4-[(8S,9S,10R,13R,14S,17R)-2-bromo-4,4,10,13-tetramethyl-3-oxo-2,7,8,9,11,12,14,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-17-yl]pentanoate
  参考文献：
  名称：

  Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B

  摘要：

  Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both insulin and leptin signals. For years, inhibiting of PTP1B has been considered to be a potential therapeutics for treating Type 2 diabetes and obesity. Recently, we recognized lithocholic acid (LCA) as a natural inhibitor against PTP1B (IC50 = 12.74 mu M) by a vertical screen for the first time. Further SAR research was carried out by synthesizing and evaluating a series of compounds bearing two methyls at C-4 position and a fused heterocycle to ring A. Among them, compound 14b achieved a PTP1B inhibitory activity about eightfold than LCA and a 14-fold selectivity over the homogenous enzyme TCPTP. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.09.040

文献信息

• Synthesis of heterocyclic ring-fused analogs of HMG499 as novel degraders of HMG-CoA reductase that lower cholesterol
  作者：Xing-Zi Li、Shi-You Jiang、Guo-Qiang Li、Qian-Ru Jiang、Jue-Wan Li、Chen-Chen Li、Yu-Qin Han、Bao-Liang Song、Xin-Ran Ma、Wei Qi、Wen-Wei Qiu

  DOI：10.1016/j.ejmech.2022.114323

  日期：2022.6

  steatohepatitis (NASH). Before, we disclosed compound HMG499 as a potent HMGCR degrader, which could be a promising agent for treating CVD, however its side-effect of promoting cholesterol accumulation in cells should be eliminated before progression. Herein, a series of novel heterocyclic ring-fused analogs of HMG499 were synthesized and investigated for their activities of stimulating HMGCR degradation using

  HMG-CoA还原酶（HMGCR）是胆固醇从头生物合成的限速酶，其降解可能为心血管疾病（CVD）和非酒精性脂肪性肝炎（NASH）的治疗带来治疗益处。之前，我们公开了化合物 HMG499 作为一种有效的 HMGCR 降解剂，它可能是治疗 CVD 的有前途的药物，但其促进细胞中胆固醇积累的副作用应在进展前消除。在此，合成了一系列新的 HMG499 杂环稠环类似物，并使用 HMGCR (TM1-8)-GFP 报告系统研究了它们刺激 HMGCR 降解的活性。其中，活性最高的化合物29 (QH536) 的 EC为 500.22 μM 促进 HMGCR 降解，其效力是 HMG499 (EC 50  = 0.43 μM)的约 2 倍。有趣的是，29与HMG499不同，它没有诱导细胞内胆固醇积累的副作用。机理研究表明，29可显着减少他汀类药物通过泛素化和通过泛素-蛋白酶体途径降解HMGCR蛋白诱导的HMG
• 胆酸衍生物及其在降胆固醇中的应用
  申请人：华东师范大学

  公开号：CN113563405B

  公开（公告）日：2023-08-08

  本发明公开了一种如式(I)所示的胆酸衍生物及其制备方法，通过TBS保护、4,4‑二甲基化、脱保护、氧化、Witting反应、还原、水解、酰化及脱保护等反应制备得到目标产物胆酸衍生物。本发明还提供了该胆酸衍生物在制备预防和/或治疗高胆固醇血症，高甘油三酯血症，和抗动脉粥样硬化以及抗非酒精性脂肪性肝炎的药物中的应用，本发明胆酸衍生物不仅能有效促进羟甲基戊二酰辅酶A还原酶(3‑hydroxy‑3‑methyl‑glutaryl‑coenzyme A reductase，HMGCR)降解，还可减少他汀类药物引起的HMGCR蛋白增多，从而降低内源性胆固醇水平，为降胆固醇新药的研发提供有益参考，具有良好的应用前景。