1-(3,4-bis(benzyloxy)phenoxy)-3-(isopropylamino)propanol | 27688-92-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 1-(3,4-bis(benzyloxy)phenoxy)-3-(isopropylamino)propanol
• 英文别名: 1-(3,4-bis(benzyloxy)phenoxy)-3-(isopropylamino)-2-propanol；XIE2008；NCI314953；1-(3,4-Dibenzyloxyphenoxy)-3-isoproylamino-2-propanol；1-(2,4-Dibenzyloxyphenoxy)-3-isopropylamino-2-propanol；1-[3,4-Bis(phenylmethoxy)phenoxy]-3-(propan-2-ylamino)propan-2-ol
• CAS: 27688-92-2
• 化学式: C₂₆H₃₁NO₄
• 分子量: 421.536
• InChiKey: CVKJFGQPZYUYQB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  31
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  60
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-(3,4-bis(benzyloxy)phenoxy)-3-(isopropylamino)propanol 在 palladium on activated charcoal 氢气 作用下， 以 甲醇 为溶剂， 生成 OXY-Isoprenaline
  参考文献：
  名称：

  Casagrande; Ferrini; Miragoli, Bollettino Chimico Farmaceutico, 1973, vol. 112, # 7, p. 445 - 454

  摘要：

  DOI：
• 作为产物：
  描述：

  [3,4-二(苯基甲氧基)苯基]乙酸酯 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 生成 1-(3,4-bis(benzyloxy)phenoxy)-3-(isopropylamino)propanol
  参考文献：
  名称：

  Casagrande; Ferrini; Miragoli, Bollettino Chimico Farmaceutico, 1973, vol. 112, # 7, p. 445 - 454

  摘要：

  DOI：

文献信息

• NOVEL P62 LIGAND COMPOUND, AND COMPOSITION CONTAINING SAME FOR PREVENTING, ALLEVIATING, OR TREATING PROTEIN ABNORMALITY DISORDERS
  申请人：Protech Co., Ltd.

  公开号：EP3828162A1

  公开（公告）日：2021-06-02

  The present invention relates to a novel p62 ligand compound, a stereoisomer, hydrate, solvate or prodrug thereof, and a pharmaceutical or food composition for preventing or treating proteinopathies comprising the same as an active ingredient. The p62 ligand compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention, amelioration or treatment of various proteinopathies by activating autophagy in cells and thus selectively eliminating in vivo proteins, organelles and aggregates.

  本发明涉及一种新型 p62 配体化合物、其立体异构体、水合物、溶质或原药，以及以其为活性成分的用于预防或治疗蛋白病的药物或食品组合物。根据本发明的 p62 配体化合物通过激活细胞自噬，从而选择性地消除体内蛋白质、细胞器和聚集物，可有效地用作药物组合物，用于预防、改善或治疗各种蛋白质病。
• Prevention and treatment of neurodegenerative diseases through autophagy activity mediated by a synthetic ligand or arginylated BIP binding to the P62 ZZ domain
  申请人：Seoul National University R&DB Foundation

  公开号：US10391067B2

  公开（公告）日：2019-08-27

  The pharmacokinetics and key technologies of the present invention are summarized in FIG. 1. Particularly, malignant misfolded proteins such as mutant huntingtin and alpha-synuclein are coagulated and grow into oligomeric coagulum (circle around (1)}, circle around (2)}, fibrillar coagulum (circle around (3)}) and eventually inclusion body (circle around (4)}). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation (circle around (5)}) of vesicle chaperones such as BiP secreted into the cytoplasm, and then arginylated BiP (R-BiP) is secreted binds to the misfolded proteins (circle around (6)}). As a ligand, the Nt-Arg of R-BiP binds to the p62 ZZ domain (circle around (7)}), and the normally inactivated closed form of p62 is changed to an open form, leading to structural activation (circle around (8)}). As a result, PB1 and LC3-binding domains are exposed. The PB1 domain induces oligomerization (circle around (9)}), leading to the concentration as a p62 body (circle around (10)}) that is a coagulum capable of being degraded by autophagy. Then, p62 binds to LC3, which is protruding from the autopagosomal membranes, leading to the completion of autophagy targeting (circle around (11)}) and lysosomal proteolysis. Since autophagy proteolysis including steps (circle around (5)})-(circle around (11)}) is strong in young neurons, cytotoxic protein coagulums (circle around (1)}-circle around (5)}) do not accumulate. However in aged neurons, autophagy proteolysis including steps circle around (5)}-circle around (11)} is weakened, and protein coagulums (circle around (1)}-circle around (5)}) accumulate and become cytotoxic. In this invention, p62 is intentionally activated (circle around (12)}, circle around (13)}) by using low mass ligands of the p62 ZZ domain to effectively remove huntingtin and alpha-synuclein protein coagulums. Particularly, in step circle around (12)}, p62 ligated with a ligand accelerates the oligomerization of p62-R-BiP-misfolded protein (circle around (9)}) and the formation of autophagy coagulum (circle around (10)}). In step (circle around (13)}), the ligand-p62 conjugate acts as an autophagy activator (circle around (14)}) to induce the synthesis of LC3 and the conversion of LC3-I into LC3-II in order to accelerate the formation of autophagosomes (circle around (15)}).

  图 1 总结了本发明的药代动力学和关键技术。尤其是恶性错误折叠蛋白质，如突变亨廷汀蛋白和α-突触核蛋白，会凝结并生长为低聚物凝块（(1)周围的圆圈}、(2)周围的圆圈}、纤维状凝块（(3)周围的圆圈}），最终形成包涵体（(4)周围的圆圈}）。年轻的神经元通过分泌到细胞质中的囊泡伴侣蛋白（如 BiP）的 N 端精氨化（(5)周围的圆圈}）产生大量 Nt-Arg，然后精氨化 BiP（R-BiP）被分泌出来与折叠错误的蛋白质结合（(6)周围的圆圈}）。作为配体，R-BiP 的 Nt-Arg 与 p62 的 ZZ 结构域结合（(7)周围的圆圈}），p62 正常失活的封闭形式转变为开放形式，导致结构活化（(8)周围的圆圈}）。因此，PB1 和 LC3 结合结构域暴露出来。PB1 结构域诱导寡聚化（(9)周围的圆圈}），导致 p62 体（(10)周围的圆圈}）浓缩，成为可被自噬降解的凝固体。然后，p62 与从自噬体膜上突出的 LC3 结合，从而完成自噬靶向（(11)}周围的圆圈）和溶酶体蛋白水解。由于年轻神经元的自噬蛋白分解（包括(5)周围的圆圈}）-（(11)周围的圆圈}）步骤很强，因此细胞毒性蛋白凝固体（(1)周围的圆圈}-(5)周围的圆圈}）不会积累。然而，在衰老的神经元中，包括(5)周围的圆圈}-(11)周围的圆圈}步骤在内的自噬蛋白水解作用减弱，蛋白质凝固体（(1)周围的圆圈}-(5)周围的圆圈}）积累并具有细胞毒性。在本发明中，通过使用 p62 ZZ 结构域的低质量配体，有意激活 p62（(12)周围的圈}、(13)周围的圈}），以有效清除亨廷蛋白和α-突触核蛋白凝集物。特别是在步骤(12)周围的圆圈}中，与配体连接的 p62 会加速 p62-R-BiP 错误折叠蛋白的寡聚化（(9)周围的圆圈}）和自噬凝固体的形成（(10)周围的圆圈}）。在步骤（(13)周围的圆圈}）中，配体-p62 共轭物作为自噬激活剂（(14)周围的圆圈}），诱导 LC3 的合成和 LC3-I 向 LC3-II 的转化，以加速自噬体的形成（(15)周围的圆圈}）。
• PREVENTION AND TREATMENT OF NEURODEGENERATIVE DISEASES THROUGH AUTOPHAGY ACTIVITY MEDIATED BY LIGAND OR ARGINYLATED BIP BINDING TO P62 ZZ DOMAIN
  申请人：AUTOTAC Bio

  公开号：EP3338787B1

  公开（公告）日：2020-03-11
• Prevention and Treatment of Neurodegenerative Diseases Through Autophagy Activity Mediated by A Synthetic Ligand or Arginylated BIP Binding to the P62 ZZ Domain
  申请人：Seoul National University R&DB Foundation

  公开号：US20180243244A1

  公开（公告）日：2018-08-30

  The pharmacokinetics and key technologies of the present invention are summarized in FIG. 1 . Particularly, malignant misfolded proteins such as mutant huntingtin and alpha-synuclein are coagulated and grow into oligomeric coagulum (circle around (1)}, circle around (2)}, fibrillar coagulum (circle around (3)}) and eventually inclusion body (circle around (4)}). Young neurons produce a large amount of Nt-Arg through N-terminal arginylation (circle around (5)}) of vesicle chaperones such as BiP secreted into the cytoplasm, and then arginylated BiP (R-BiP) is secreted binds to the misfolded proteins (circle around (6)}). As a ligand, the Nt-Arg of R-BiP binds to the p62 ZZ domain (circle around (7)}), and the normally inactivated closed form of p62 is changed to an open form, leading to structural activation (circle around (8)}). As a result, PB1 and LC3-binding domains are exposed. The PB1 domain induces oligomerization (circle around (9)}), leading to the concentration as a p62 body (circle around (10)}) that is a coagulum capable of being degraded by autophagy. Then, p62 binds to LC3, which is protruding from the autopagosomal membranes, leading to the completion of autophagy targeting (circle around (11)}) and lysosomal proteolysis. Since autophagy proteolysis including steps (circle around (5)})-(circle around (11)}) is strong in young neurons, cytotoxic protein coagulums (circle around (1)}-circle around (5)}) do not accumulate. However in aged neurons, autophagy proteolysis including steps circle around (5)}-circle around (11)} is weakened, and protein coagulums (circle around (1)}-circle around (5)}) accumulate and become cytotoxic. In this invention, p62 is intentionally activated (circle around (12)}, circle around (13)}) by using low mass ligands of the p62 ZZ domain to effectively remove huntingtin and alpha-synuclein protein coagulums. Particularly, in step circle around (12)}, p62 ligated with a ligand accelerates the oligomerization of p62-R-BiP-misfolded protein (circle around (9)}) and the formation of autophagy coagulum (circle around (10)}). In step (circle around (13)}), the ligand-p62 conjugate acts as an autophagy activator (circle around (14)}) to induce the synthesis of LC3 and the conversion of LC3-I into LC3-II in order to accelerate the formation of autophagosomes (circle around (15)}).
• NOVEL P62 LIGAND COMPOUND, AND COMPOSITION FOR PREVENTING, AMELIORATING OR TREATING PROTEINOPATHIES COMPRING THE SAME
  申请人：PROTECH Co., Ltd.

  公开号：US20210347749A1

  公开（公告）日：2021-11-11

  The present invention relates to a novel p62 ligand compound, a stereoisomer, hydrate, solvate or prodrug thereof, and a pharmaceutical or food composition for preventing or treating proteinopathies comprising the same as an active ingredient. The p62 ligand compound according to the present invention can be usefully used as a pharmaceutical composition for the prevention, amelioration or treatment of various proteinopathies by activating autophagy in cells and thus selectively eliminating in vivo proteins, organelles and aggregates.