(S,3S,3'S,6S,6'S,10aS,10a'S)-N,N'-((1S,1'S)-(1,1'-(4,4'-(1,4-phenylene)bis(butane-4,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(phenylmethylene))bis(6-((S)-2-(2-methylamino)propanamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide) | 957135-43-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S,3S,3'S,6S,6'S,10aS,10a'S)-N,N'-((1S,1'S)-(1,1'-(4,4'-(1,4-phenylene)bis(butane-4,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(phenylmethylene))bis(6-((S)-2-(2-methylamino)propanamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide)
• 英文别名: SM59；SM-164；HY-15989；(3S,3'S,6S,6'S,10aS,10a'S)-N,N'-((1S,1'S)-((1,4-phenylenebis(butane-4,1-diyl))bis(1H-1,2,3-triazole-1,4-diyl))bis(phenylmethylene))bis(6-((S)-2-(methylamino)propanamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide)；(3S,6S,10aS)-N-[(S)-[1-[4-[4-[4-[4-[(S)-[[(3S,6S,10aS)-6-[[(2S)-2-(methylamino)propanoyl]amino]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocine-3-carbonyl]amino]-phenylmethyl]triazol-1-yl]butyl]phenyl]butyl]triazol-4-yl]-phenylmethyl]-6-[[(2S)-2-(methylamino)propanoyl]amino]-5-oxo-2,3,6,7,8,9,10,10a-octahydro-1H-pyrrolo[1,2-a]azocine-3-carboxamide
• CAS: 957135-43-2
• 化学式: C₆₂H₈₄N₁₄O₆
• 分子量: 1121.44
• InChiKey: LGYDZXNSSLRFJS-IOQQVAQYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  82
• 可旋转键数：
  24
• 环数：
  9.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  243
• 氢给体数：
  6
• 氢受体数：
  12

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

反应信息

• 作为产物：
  描述：

  在 盐酸 作用下， 以 1,4-二氧六环 、 甲醇 为溶剂， 生成 (S,3S,3'S,6S,6'S,10aS,10a'S)-N,N'-((1S,1'S)-(1,1'-(4,4'-(1,4-phenylene)bis(butane-4,1-diyl))bis(1H-1,2,3-triazole-4,1-diyl))bis(phenylmethylene))bis(6-((S)-2-(2-methylamino)propanamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide)
  参考文献：
  名称：

  Design, Synthesis, and Characterization of a Potent, Nonpeptide, Cell-Permeable, Bivalent Smac Mimetic That Concurrently Targets Both the BIR2 and BIR3 Domains in XIAP

  摘要：

  XIAP is a central apoptosis regulator that inhibits apoptosis by binding to and inhibiting the effectors caspase-3/-7 and an initiator caspase-9 through its BIR2 and BIR3 domains, respectively. Smac protein in its dimeric form effectively antagonizes XIAP by concurrently, targeting both its BIR2 and BIR3 domains. We report the design, synthesis, and characterization of a nonpeptide, cell-permeable, bivalent small-molecule (SM-164) which mimics Smac protein for targeting XIAP. Our study shows that SM-164 binds to XIAP containing both BIR domains with an IC50 value of 1.39 nM, being 300 and 7000 times more potent than its monovalent counterparts and the natural Smac AVPI peptide, respectively. SM-164 concurrently interacts with both BIR domains in XIAP and functions as an ultrapotent antagonist of XIAP in both cell-free functional and cell-based assays. SM-164 targets cellular XIAP and effectively induces apoptosis at concentrations as low as 1 nM in the HL-60 leukemia cell line. The potency of bivalent SM-164 in binding, functional, and cellular assays is 2-3 orders of magnitude higher than its corresponding monovalent Smac mimetics.

  DOI：

  10.1021/ja074725f

文献信息

• COMPOUNDS AND METHODS FOR THE TARGETED DEGRADATION OF INTERLEUKIN-1 RECEPTOR-ASSOCIATED KINASE 4 POLYPEPTIDES
  申请人：Arvinas, Inc.

  公开号：US20190151295A1

  公开（公告）日：2019-05-23

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，其作为白细胞介素-1受体相关激酶4（IRAK-4；目标蛋白）的调节剂具有实用性。具体而言，本公开涉及包含一端结合E3泛素连接酶的Von Hppel-Lindau、cereblon配体的双功能化合物，另一端结合目标蛋白的部分，使得目标蛋白靠近泛素连接酶以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白的降解/抑制相关的广泛药理活性。本公开的化合物和组合物用于治疗或预防由目标蛋白聚集或积累导致的疾病或紊乱。
• TETRAHYDRONAPHTHALENE AND TETRAHYDROISOQUINOLINE DERIVATIVES AS ESTROGEN RECEPTOR DEGRADERS
  申请人：Arvinas, Inc.

  公开号：US20180155322A1

  公开（公告）日：2018-06-07

  The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end at least one of a Von Hippel-Lindau ligand, a cereblon ligand, Inhibitors of Apoptosis Proteins ligand, mouse double-minute homolog 2 ligand, or a combination thereof, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，这些化合物可用作雌激素受体（目标蛋白）的调节剂。特别是，本公开涉及包含在一段至少有一种Von Hippel-Lindau配体、一种cereblon配体、凋亡抑制蛋白配体、小鼠双分钟同源2配体或其组合的双功能化合物，这些配体与相应的E3泛素连接酶结合，在另一端有一个与目标蛋白结合的部分，使得目标蛋白被置于泛素连接酶附近，以实现目标蛋白的降解（和抑制）。本公开展示了与目标蛋白降解/抑制相关的广泛药理活性。可以通过本公开的化合物和组合物治疗或预防由目标蛋白聚集或积累引起的疾病或障碍。
• Tetrahydronaphthalene and tetrahydroisoquinoline derivatives as estrogen receptor degraders
  申请人：Arvinas, Inc.

  公开号：US10647698B2

  公开（公告）日：2020-05-12

  The present disclosure relates to bifunctional compounds, which find utility as modulators of estrogen receptor (target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end at least one of a Von Hippel-Lindau ligand, a cereblon ligand, Inhibitors of Apoptosis Proteins ligand, mouse double-minute homolog 2 ligand, or a combination thereof, which binds to the respective E3 ubiquitin ligase, and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，它们可用作雌激素受体（靶蛋白）的调节剂。特别是，本公开涉及双功能化合物，其一端含有 Von Hippel-Lindau 配体、cereblon 配体、凋亡蛋白抑制剂配体、小鼠双敏同源物 2 配体或其组合中的至少一种、其一端与相应的 E3 泛素连接酶结合，另一端与靶蛋白结合，从而将靶蛋白置于泛素连接酶附近，以实现对靶蛋白的降解（和抑制）。本公开物具有与降解/抑制靶蛋白相关的广泛药理活性。本公开的化合物和组合物可以治疗或预防因目标蛋白聚集或积聚而导致的疾病或失调。
• EGFR proteolysis targeting chimeric molecules and associated methods of use
  申请人：Arvinas Operations, Inc.

  公开号：US10994015B2

  公开（公告）日：2021-05-04

  The present disclosure relates to bifunctional compounds, which find utility as modulators of receptor tyrosine kinase (RTK) proteins. In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a ligand which binds to an E3 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 effectuate ubiquitination, and therefore, degradation (and inhibition) of the target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，它们可用作受体酪氨酸激酶（RTK）蛋白的调节剂。特别是，本公开涉及双功能化合物，其一端含有与 E3 泛素连接酶结合的配体，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泛素化，进而降解（和抑制）靶蛋白。本公开内容展示了与靶蛋白降解/抑制相关的广泛药理活性。本公开的化合物和组合物可以治疗或预防因目标蛋白聚集或积聚而导致的疾病或失调。
• Compounds and methods for the targeted degradation of interleukin-1 receptor- associated kinase 4 polypeptides
  申请人：Arvinas Operations, Inc.

  公开号：US11065231B2

  公开（公告）日：2021-07-20

  The present disclosure relates to bifunctional compounds, which find utility as modulators of Interleukin-1 Receptor-Associated Kinase 4 (IRAK-4); the target protein). In particular, the present disclosure is directed to bifunctional compounds, which contain on one end a Von Hppel-Lindau, cereblon, ligand which binds to the E3 ubiquitin ligase and on the other end a moiety which binds the target protein, such that the target protein is placed in proximity to the ubiquitin ligase to effect degradation (and inhibition) of target protein. The present disclosure exhibits a broad range of pharmacological activities associated with degradation/inhibition of target protein. Diseases or disorders that result from aggregation or accumulation of the target protein are treated or prevented with compounds and compositions of the present disclosure.

  本公开涉及双功能化合物，这些化合物可作为白细胞介素-1受体相关激酶4（IRAK-4）（靶蛋白）的调节剂。特别是，本公开涉及双功能化合物，其一端含有与 E3 泛素连接酶结合的 Von Hppel-Lindau（脑龙）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，以实现对靶蛋白的降解（和抑制）。本公开物具有与降解/抑制靶蛋白相关的广泛药理活性。本公开的化合物和组合物可以治疗或预防因目标蛋白聚集或积聚而导致的疾病或失调。