(E)-3-(4-((E)-1-(1H-indol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (E)-3-(4-((E)-1-(1H-indol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid
• 英文别名: (E)-3-[4-[(E)-1-(1H-indol-5-yl)-2-phenylbut-1-enyl]phenyl]prop-2-enoic acid
• 化学式: C₂₇H₂₃NO₂
• 分子量: 393.485
• InChiKey: NNQKLLSZBAAXTB-UXNQVWTBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  53.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  5-碘吲哚 在 盐酸 、 4-二甲氨基吡啶 、 copper(l) iodide 、 二(氰基苯)二氯化钯 、 四(三苯基膦)钯 、 四丁基氟化铵 、 三苯基氯甲烷 、 potassium carbonate 、 lithium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 1,2-二氯乙烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (E)-3-(4-((E)-1-(1H-indol-5-yl)-2-phenylbut-1-en-1-yl)phenyl)acrylic acid
  参考文献：
  名称：

  Identification of GDC-0810 (ARN-810), an Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) that Demonstrates Robust Activity in Tamoxifen-Resistant Breast Cancer Xenografts

  摘要：

  Approximately 80% of breast cancers are estrogen receptor alpha, (ER-a) positive, and although women typically initially respond, well to antihormonal therapies such as tamoxifen and aromatase inhibitors, resistance often emerges. Although a variety of resistance mechanism may be at play in this state, there is evidence that in many cases the ER still plays a central role, including mutations in the ER leading to constitutively active receptor. Fulvestrant is a steroid-based, selective estrogen receptor degrader., (SEED) That both antagonizes and degrades ER-alpha and is active in patients who have progressed on antihormonal agents. However, fulvestrant suffers from poor pharmaceutical properties and must be administered by intramuscular injections that limit the total amount of drug that can be administered and hence lead to the potential for incomplete receptor blockade. We describe the identification and characterization of a series of small-molecule, orally bioavailable SERDs, which are potent antagonists and degraders of ER-alpha and in which the ER-alpha degrading properties were prospectively optimized. The lead compound 111 (GDC-0810 or ARN-810) demonstrates robust activity in models of tamoxifen-sensitive and tamoxifen-resistant breast cancer, and is currently in clinical trials in women with locally advanced or metastatic estrogen receptor-positive breast cancer.

  DOI：

  10.1021/acs.jmedchem.5b00054

文献信息

• ESTROGEN RECEPTOR MODULATORS AND USES THEREOF
  申请人：Smith Nicholas D.

  公开号：US20130231333A1

  公开（公告）日：2013-09-05

  Described herein are compounds that are estrogen receptor modulators. Also described are pharmaceutical compositions and medicaments that include the compounds described herein, as well methods of using such estrogen receptor modulators, alone and in combination with other compounds, for treating diseases or conditions that are mediated or dependent upon estrogen receptors.

  本文描述了一些雌激素受体调节剂化合物。还描述了包括所述化合物的制药组合物和药物，以及使用这些雌激素受体调节剂，单独或与其他化合物结合，治疗与雌激素受体介导或依赖的疾病或症状的方法。
• Estrogen receptor modulators and uses thereof
  申请人：Seragon Pharmaceuticals, Inc.

  公开号：EP2735562A1

  公开（公告）日：2014-05-28

  A compound that has the structure of Formula (XII): wherein, X1 is CH, CR3 or N; X2 is N, CH, or CR3; Z is -OH or -OR10; R2 is C1-C4alkyl, C1-C4fluoroalkyl, C1-C4deuteroalkyl, C3-C6cycloalkyl, or -C1-C4alkylene-W; W is hydroxy, halogen, CN, C1-C4alkyl, C1-C4haloalkyl, C1-C4alkoxy, C1-C4haloalkoxy, and C3-C6cycloalkyl; each R3 is independently halogen, C1-C4alkyl, or C1-C4fluoroalkyl; each R4 is independently halogen, -CN, -OR9, -S(=O)2R10, C1-C4alkyl, C1-C4fluoroalkyl, or C1-C4heteroalkyl; each R5 is independently halogen, -CN, -OR9, -S(=O)2R10, C1-C4alkyl, C1-C4fluoroalkyl, or C1-C4heteroalkyl; R6 is H, C1-C4alkyl, or halogen; R7 is H, C1-C4alkyl, or halogen; R9 is H, C1-C6alkyl, C1-C6fluoroalkyl, or C3-C6cycloalkyl; R10 is C1-C6alkyl; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and p is 0, 1, or 2; or a pharmaceutically acceptable or N-oxide thereof.

  具有式 (XII) 结构的化合物： 其中 X1 是 CH、CR3 或 N； X2 是 N、CH 或 CR3 Z 是-OH 或-OR10； R2 是 C1-C4 烷基、C1-C4 氟烷基、C1-C4 丁烷基、C3-C6 环烷基或-C1-C4 亚烷基-W； W 是羟基、卤素、CN、C1-C4 烷基、C1-C4 卤代烷基、C1-C4 烷氧基、C1-C4 卤代烷氧基和 C3-C6 环烷基； 每个 R3 独立地为卤素、C1-C4 烷基或 C1-C4 氟烷基； 每个 R4 独立地为卤素、-CN、-OR9、-S(=O)2R10、C1-C4 烷基、C1-C4 氟烷基或 C1-C4 异烷基； 每个 R5 独立地是卤素、-CN、-OR9、-S(=O)2R10、C1-C4 烷基、C1-C4 氟烷基或 C1-C4 异烷基； R6 是 H、C1-C4 烷基或卤素； R7 是 H、C1-C4 烷基或卤素； R9 是 H、C1-C6 烷基、C1-C6 氟烷基或 C3-C6 环烷基； R10 是 C1-C6 烷基； m 是 0、1 或 2； n 是 0、1、2、3 或 4；以及 p 是 0、1 或 2； 或其药学上可接受的或 N-氧化物。
• Estrogen receptor mutations and uses thereof
  申请人：FOUNDATION MEDICINE, INC.

  公开号：US10093983B2

  公开（公告）日：2018-10-09

  Novel mutant ESR1 molecules and uses are disclosed.

  公开了新型突变 ESR1 分子及其用途。
• Diagnostic and therapeutic methods for the treatment of breast cancer
  申请人：GENENTECH, INC.

  公开号：US11081236B2

  公开（公告）日：2021-08-03

  Provided herein, inter alia, are predictive diagnostic, pharmacodynamic, and therapeutic methods for the treatment of breast cancer. In embodiments, the methods and compositions are based, at least in part, on the discovery that the estradiol (E2)-induced score or estrogen receptor (ER) pathway activity score determined from a sample (e.g., a tissue sample, e.g., a tumor tissue sample, e.g., a FFPE, a FF, an archival, a fresh, or a frozen tumor tissue sample) from an individual can be used in methods of determining whether the individual having breast cancer is likely to respond to a treatment including an endocrine therapy, selecting a therapy for an individual having breast cancer; treating an individual having breast cancer; and monitoring therapeutic efficacy of an endocrine therapy, as well as related kits.

  本文特别提供了治疗乳腺癌的预测性诊断、药效学和治疗方法。在实施方案中，这些方法和组合物至少部分基于以下发现：从样本（如组织样本，如肿瘤组织样本，如 FFPE、FF、存档样本、新鲜样本或ER）中确定的雌二醇（E2）诱导评分或雌激素受体（ER）通路活性评分、FFPE、FF、存档、新鲜或冷冻肿瘤组织样本）可用于确定乳腺癌患者是否可能对包括内分泌疗法在内的治疗产生反应、为乳腺癌患者选择疗法、治疗乳腺癌患者和监测内分泌疗法疗效的方法以及相关试剂盒。
• [EN] ESTROGEN RECEPTOR MODULATORS AND USES THEREOF<br/>[FR] MODULATEURS DES RÉCEPTEURS DES OESTROGÈNES ET LEURS UTILISATIONS
  申请人：ARAGON PHARMACEUTICALS INC

  公开号：WO2012037411A9

  公开（公告）日：2012-05-18