18-((7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-13-methyl-4,7,10-trioxa-13-azaoctadecan-1-oic acid | 1448189-25-0

• 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: 18-((7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-13-methyl-4,7,10-trioxa-13-azaoctadecan-1-oic acid
• 英文别名: 3-[2-[2-[2-[5-[(7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-7-yl]pentyl-methylamino]ethoxy]ethoxy]ethoxy]propanoic acid
• CAS: 1448189-25-0
• 化学式: C₃₃H₅₃NO₇
• 分子量: 575.786
• InChiKey: CJIWTEDDDKQSGB-XEXYCPDTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  41
• 可旋转键数：
  18
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  109
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  18-((7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-13-methyl-4,7,10-trioxa-13-azaoctadecan-1-oic acid 、 （2S,4R）-1-（（S）-2-氨基-3,3-二甲基丁酰基）-4-羟基-N-（4-（4-甲基噻唑-5-基）苄基）吡咯烷-2-甲酰胺盐酸盐 在 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.17h， 以68%的产率得到(2S,4R)-1-((S)-2-(tert-butyl)-21-((7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-16-methyl-4-oxo-7,10,13-trioxa-3,16-diazahenicosan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide
  参考文献：
  名称：

  [EN] PROTEOLYSIS TARGETING CHIMERAS (PROTACS) DIRECTED TO THE MODULATION OF THE ESTROGEN RECEPTOR
  [FR] CHIMÈRES CIBLANT LA PROTÉOLYSE (PROTACS) DIRIGÉES VERS LA MODULATION DU RÉCEPTEUR DES ŒSTROGÈNES

  摘要：

  公式（I）的化合物：或其药用可接受盐，含有所述化合物的组合物、组合物和药物以及其制备方法。本发明还涉及所述化合物、组合物、组合物和药物的用途，例如作为雌激素受体活性的抑制剂，包括降解雌激素受体，治疗由雌激素受体介导的疾病和症状。

  公开号：

  WO2014108452A1
• 作为产物：
  描述：

  (7R,8R,9S,13S,14S,17S)-7-(5-(benzyloxy)pentyl)-3,17-bis(methoxymethoxy)-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthrene 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 吡啶 、 乙醇 、 甲基叔丁基醚 、 水 为溶剂， 反应 75.5h， 生成 18-((7R,8R,9S,13S,14S,17S)-3,17-dihydroxy-13-methyl-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-7-yl)-13-methyl-4,7,10-trioxa-13-azaoctadecan-1-oic acid
  参考文献：
  名称：

  [EN] PROTEOLYSIS TARGETING CHIMERAS (PROTACS) DIRECTED TO THE MODULATION OF THE ESTROGEN RECEPTOR
  [FR] CHIMÈRES CIBLANT LA PROTÉOLYSE (PROTACS) DIRIGÉES VERS LA MODULATION DU RÉCEPTEUR DES ŒSTROGÈNES

  摘要：

  公式（I）的化合物：或其药用可接受盐，含有所述化合物的组合物、组合物和药物以及其制备方法。本发明还涉及所述化合物、组合物、组合物和药物的用途，例如作为雌激素受体活性的抑制剂，包括降解雌激素受体，治疗由雌激素受体介导的疾病和症状。

  公开号：

  WO2014108452A1

文献信息

• Compounds & Methods for the Enhanced Degradation of Targeted Proteins & Other Polypeptides by an E3 Ubiquitin Ligase
  申请人：YALE UNIVERSITY

  公开号：US20140356322A1

  公开（公告）日：2014-12-04

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，其作为靶向泛素化的调节剂具有实用性，特别是作为本发明的双功能化合物对各种被降解和/或受到抑制的多肽和其他蛋白质的抑制剂。具体而言，本发明涉及含有一端结合泛素连接酶的VHL配体，另一端结合靶蛋白的基团的化合物，使得靶蛋白靠近泛素连接酶以促使该蛋白的降解（和抑制）。本发明展示了与本发明化合物相关的广泛的药理活性范围，与靶向多肽的降解/抑制一致。
• COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE
  申请人：Yale University

  公开号：EP3608317A1

  公开（公告）日：2020-02-12

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，它们可作为靶向泛素化的调节剂，特别是可被根据本发明的双功能化合物降解和/或以其他方式抑制的各种多肽和其他蛋白质。特别是，本发明涉及的化合物一端含有与泛素连接酶结合的 VHL 配体，另一端含有与靶蛋白结合的分子，从而使靶蛋白靠近泛素连接酶，以实现对该蛋白的降解（和抑制）。本发明显示了与根据本发明的化合物相关的广泛的药理活性，与降解/抑制靶向多肽一致。
• Compounds and methods for the enhanced degradation of targeted proteins and other polypeptides by an E3 ubiquitin ligase
  申请人：YALE UNIVERSITY

  公开号：US10730862B2

  公开（公告）日：2020-08-04

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins that are degraded and/or otherwise inhibited by bifunctional compounds of the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand that binds to the ubiquitin ligase and on the other end a moiety that binds a target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds of the present invention, consistent with the degradation/inhibition of targeted polypeptides.

  本发明涉及双功能化合物，它们可作为靶向泛素化的调节剂，特别是本发明双功能化合物降解和/或以其他方式抑制的各种多肽和其他蛋白质的抑制剂。特别是，本发明涉及的化合物一端含有与泛素连接酶结合的 VHL 配体，另一端含有与靶蛋白结合的分子，从而使靶蛋白靠近泛素连接酶，以达到降解（和抑制）该蛋白的效果。本发明显示了与本发明化合物相关的广泛药理活性，与降解/抑制靶向多肽的作用相一致。
• [EN] COMPOUNDS & METHODS FOR THE ENHANCED DEGRADATION OF TARGETED PROTEINS & OTHER POLYPEPTIDES BY AN E3 UBIQUITIN LIGASE<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR LA DÉGRADATION AMÉLIORÉE DE PROTÉINES CIBLES ET D'AUTRES POLYPEPTIDES PAR UNE E3 UBIQUITINE LIGASE
  申请人：UNIV YALE

  公开号：WO2013106643A2

  公开（公告）日：2013-07-18

  The present invention relates to bifunctional compounds, which find utility as modulators of targeted ubiquitination, especially inhibitors of a variety of polypeptides and other proteins which are degraded and/or otherwise inhibited by bifunctional compounds according to the present invention. In particular, the present invention is directed to compounds, which contain on one end a VHL ligand which binds to the ubiquitin ligase and on the other end a moiety which binds a target protein such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of that protein. The present invention exhibits a broad range of pharmacological activities associated with compounds according to the present invention, consistent with the degradation/inhibition of targeted polypeptides.
• [EN] COMPOUNDS AND METHODS FOR THE INHIBITION OF VCB E3 UBIQUITIN LIGASE<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR L'INHIBITION DE L'UBIQUITINE LIGASE VCB E3
  申请人：UNIV YALE

  公开号：WO2013106646A2

  公开（公告）日：2013-07-18

  The present invention relates to novel compounds which find utility as modulators, especially inhibitors of VCB E3 Ubiquitin Ligase and as bioactive agents for use as therapeutics for the stimulation of erythropoiesis in a patient or subject including inducement of EPO production in the patient or subject, for the treatment of chronic anemia and ischemia (limits brain injury during episodes of localized anemia, ischemia and/or stroke and damage to cardiovascular tissue during cardiovascular ischemia), as well as enhancing wound healing processes. Pharmaceutical compositions comprising effective amounts of compounds according to the present invention alone or in combination with an additional erythropoieses stimulating agent such as EPO under the tradename procrit or epogen or darbapoietin alfa under the tradename aranesp. Methods of stimulating erythropoiesis in a subject or patient, including increasing the number of red blood cells and/or hematocrit of the patient, treating anemia, including chronic anemia and anemia associated with chronic kidney disease, dialysis, and cancer chemotherapy, ischemia, stroke and damage to cardiovascular tissue during cardiovascular ischemia as well as enhancing wound healing processes and preventing/reducing scarring secondary to healing represent additional aspects of the present invention. Local enhancement of angiogenesis through induction of VEGF including wound healing and reduction of stent occlusion remain additional aspects of the present invention.