2-methoxyethoxymethyl (3aS,4S,5S,7S,7aR)-2-[4-cyano-3-(trifluoromethyl)phenyl]-4,7-dimethyl-1,3-dioxo-3a,5,6,7a-tetrahydro-4,7-epoxyisoindole-5-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-methoxyethoxymethyl (3aS,4S,5S,7S,7aR)-2-[4-cyano-3-(trifluoromethyl)phenyl]-4,7-dimethyl-1,3-dioxo-3a,5,6,7a-tetrahydro-4,7-epoxyisoindole-5-carboxylate
• 化学式: C₂₃H₂₃F₃N₂O₇
• 分子量: 496.44
• InChiKey: HTANSGKHUNBSEE-OKYVINKXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.41
• 重原子数：
  35.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  115.16
• 氢给体数：
  0.0
• 氢受体数：
  8.0

反应信息

• 作为反应物：
  描述：

  2-methoxyethoxymethyl (3aS,4S,5S,7S,7aR)-2-[4-cyano-3-(trifluoromethyl)phenyl]-4,7-dimethyl-1,3-dioxo-3a,5,6,7a-tetrahydro-4,7-epoxyisoindole-5-carboxylate 在 盐酸 、 叠氮磷酸二苯酯 、 水 、 三乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 正庚烷 、 二氯甲烷 为溶剂， 反应 21.0h， 生成 BMS-641988
  参考文献：
  名称：

  Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

  摘要：

  BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

  DOI：

  10.1021/acsmedchemlett.5b00173
• 作为产物：
  描述：

  4-氨基-2-三氟甲基苯甲腈 在 palladium 10% on activated carbon 、 氢气 、 溶剂黄146 作用下， 以 乙酸乙酯 为溶剂， 反应 1.5h， 生成 2-methoxyethoxymethyl (3aS,4S,5S,7S,7aR)-2-[4-cyano-3-(trifluoromethyl)phenyl]-4,7-dimethyl-1,3-dioxo-3a,5,6,7a-tetrahydro-4,7-epoxyisoindole-5-carboxylate
  参考文献：
  名称：

  Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer

  摘要：

  BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.

  DOI：

  10.1021/acsmedchemlett.5b00173

文献信息

• [EN] ANDROGEN RECEPTOR REGULATION BY SMALL MOLECULE ENANTIOMERS<br/>[FR] RÉGULATION DU RÉCEPTEUR DES ANDROGÈNES PAR DES ÉNANTIOMÈRES DE PETITES MOLÉCULES
  申请人：UNIV SOUTHERN CALIFORNIA

  公开号：WO2021189051A1

  公开（公告）日：2021-09-23

  Herein is reported a class of chiral compounds with paradoxical effects on the androgen receptor (AR). The (R)-enantiomers behave like classical anti-androgens while the (S)-enantiomers activate AR signaling. In castration-resistant prostate cancer, the change during the course of therapy to growth in the presence of AR targeted therapeutics, a harbinger of progression to lethal disease, is commonly attributed to acquired mutations of the AR-ligand binding domain. This is the first report of an antagonist -agonist duality solely due to structural enantiomerism, without any modification to the AR binding site.

  这里报告了一类手性化合物，对雄激素受体（AR）具有矛盾的影响。 （R）-对映体的行为类似于经典的抗雄激素，而（S）-对映体激活AR信号传导。在去势耐药性前列腺癌中，疗程中转变为在AR靶向治疗存在下的生长，这是一个致命疾病进展的前兆，通常被归因于AR配体结合结构域的获得性突变。这是首次报道了由于结构对映异构体而产生的拮抗剂-激动剂二重性，而无需对AR结合位点进行任何修改。
• Discovery of BMS-641988, a Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer
  作者：Aaron Balog、Richard Rampulla、Gregory S. Martin、Stanley R. Krystek、Ricardo Attar、Janet Dell-John、John D. DiMarco、David Fairfax、Jack Gougoutas、Christian L. Holst、Andrew Nation、Cheryl Rizzo、Lana M. Rossiter、Liang Schweizer、Weifang Shan、Steven Spergel、Thomas Spires、Georgia Cornelius、Marco Gottardis、George Trainor、Gregory D. Vite、Mark E. Salvati

  DOI：10.1021/acsmedchemlett.5b00173

  日期：2015.8.13

  BMS-641988 (23) is a novel, nonsteroidal androgen receptor antagonist designed for the treatment of prostate cancer. The compound has high binding affinity for the AR and acts as a functional antagonist in vitro. BMS-641988 is efficacious in multiple human prostate cancer xenograft models, including CWR22-BMSLD1 where it displays superior efficacy relative to bicalutamide. Based on its promising preclinical profile, BMS-641988 was selected for clinical development.