(E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid | 2088518-51-6

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
• 英文别名: G1T48；Rintodestrant；(E)-3-[4-[[2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxy-1-benzothiophen-3-yl]oxy]phenyl]prop-2-enoic acid
• CAS: 2088518-51-6
• 化学式: C₂₆H₁₉FO₅S
• 分子量: 462.498
• InChiKey: KOAITBOFZOEDOC-BJMVGYQFSA-N

物化性质

• 沸点：
  649.9±55.0 °C(Predicted)
• 密度：
  1.390±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.6
• 重原子数：
  33
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  112
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-溴-5-氯-1,3-二甲基苯 在 bis-triphenylphosphine-palladium(II) chloride 、 三氟二甲基硫醚络合物 、 碘 、 caesium carbonate 、 magnesium 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 (E)-3-(4-((2-(4-fluoro-2,6-dimethylbenzoyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid
  参考文献：
  名称：

  Novel Selective Estrogen Receptor Downregulators (SERDs) Developed against Treatment-Resistant Breast Cancer

  摘要：

  Resistance to the selective estrogen receptor modulator tamoxifen and to aromatase inhibitors that lower circulating estradiol occurs in up to 50% of patients, generally leading to an endocrine-independent ER+ phenotype. Selective ER downregulators (SERDs) are able to ablate ER and thus, theoretically, to prevent survival of both endocrine-dependent and -independent ER+ tumors. The clinical SERD fulvestrant is hampered by intramuscular administration and undesirable pharmacokinetics. Novel SERDs were designed using the 6-OH-benzothiophene (BT) scaffold common to arzoxifene and raloxifene. Treatment-resistant (TR) ER+ cell lines (MCF-7:5C and MCF-7:TAM1) were used for optimization, followed by validation in the parent endocrine-dependent cell line (MCF-7:WS8), in 2D and 3D cultures, using ER alpha in-cell westerns, ERE-luciferase, and cell viability assays, with 2 (GDC-0810/ARN-810) used for comparison. Two BT SERDs with superior in vitro activity to 2 were studied for bioavailability and shown to cause regression of a TR, endocrine -independent ER+ xenograft superior to that with 2.

  DOI：

  10.1021/acs.jmedchem.6b01355

文献信息

• [EN] CYCLIN-DEPENDENT KINASE INHIBITING COMPOUNDS FOR THE TREATMENT OF MEDICAL DISORDERS<br/>[FR] COMPOSÉS INHIBITEURS DE KINASE DÉPENDANT DE LA CYCLINE POUR LE TRAITEMENT D'AFFECTIONS MÉDICALES
  申请人：G1 THERAPEUTICS INC

  公开号：WO2021236650A1

  公开（公告）日：2021-11-25

  This invention is in the area of cell cycle inhibiting compounds for the treatment of disorders involving abnormal cellular proliferation, and include selective CDK2 inhibitors for medical therapy and their pharmaceutically acceptable salts and compositions.

  这项发明涉及细胞周期抑制化合物领域，用于治疗涉及异常细胞增殖的疾病，包括用于医学治疗的选择性CDK2抑制剂及其药用盐和组合物。
• Benzothiophene-based selective estrogen receptor downregulators
  申请人：The Board of Trustees of the University of Illinois

  公开号：US10118910B2

  公开（公告）日：2018-11-06

  This invention is benzothiophene-based estrogen receptor downregulators and their compositions and uses to treat estrogen-related medical disorders.

  本发明是苯并噻吩类雌激素受体下调剂及其组合物，用于治疗雌激素相关疾病。
• Benzothiophene-based selective estrogen receptor downregulator compounds
  申请人：The Board of Trustees of the University of Illinois

  公开号：US11072595B2

  公开（公告）日：2021-07-27

  This invention is benzothiophene-based estrogen receptor downregulators and their compositions and uses to treat estrogen-related medical disorders.

  本发明是苯并噻吩类雌激素受体下调剂及其组合物，用于治疗雌激素相关疾病。
• 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。
• Combination therapy for treatment of cancer
  申请人：G1 Therapeutics, Inc.

  公开号：US11364222B2

  公开（公告）日：2022-06-21

  Compositions, combinations and methods comprising a CDK4/6 inhibitor of Formula D with a selective estrogen receptor downregulator of Formula A, B or C that are advantageous for the treatment of abnormal cellular proliferation, including a cancer or a tumor.

  由式D的CDK4/6抑制剂与式A、B或C的选择性雌激素受体下调剂组成的组合物、组合物和方法，有利于治疗异常细胞增殖，包括癌症或肿瘤。