(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide
• 英文别名: (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(5-fluoro-3-methylindol-1-yl)-2-hydroxy-2-methylpropanamide
• 化学式: C₂₁H₁₇F₄N₃O₂
• 分子量: 419.378
• InChiKey: DAXZYVGQYZDTFR-FQEVSTJZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  78
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-氨基-2-三氟甲基苯甲腈 在 氯化亚砜 、 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 丙酮 、 mineral oil 为溶剂， 反应 1.0h， 生成 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(5-fluoro-3-methyl-1H-indol-1-yl)-2-hydroxy-2-methylpropanamide
  参考文献：
  名称：

  新一代选择性雄激素受体降解剂：我们具有恩杂鲁胺抗性前列腺癌活性的新化合物的初步设计，合成和生物学评估

  摘要：

  在寻找晚期前列腺癌（PCs）的小分子治疗方法的过程中，发现了一系列新颖的吲哚基和吲哚基丙酰胺（II和III系列）作为选择性雄激素受体降解剂（SARDs）。对雄激素受体（AR）拮抗剂（1）和激动剂（2）丙酰胺的初步研究产生了具有新型SARD活性但代谢稳定性较差的叔苯胺（3）。环化至II和III产生亚微摩尔的AR拮抗作用，并对AR和AR剪接变体（AR SV）产生选择性的蛋白质降解。二和三维持对enzalutamide耐药（Enz-R）突变的ARs和PC细胞的效力，并且对Enz-R异种移植物有效，表明它们具有治疗晚期PCs的潜力。新型SARD的设计，合成和生物学活性，可潜在地用于治疗各种PC，包括去势抵抗性，Enz-R和/或AR SV依赖性的晚期PC，这些已知PC通常无法用已知的激素疗法治疗讨论。

  DOI：

  10.1021/acs.jmedchem.8b00973

文献信息

• [EN] SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF<br/>[FR] LIGANDS DE SARD - COMPOSÉS DE DÉGRADATION SÉLECTIFS DES RÉCEPTEURS AUX ANDROGÈNES - ET MÉTHODES D'UTILISATION
  申请人：GTX INC

  公开号：WO2016172358A1

  公开（公告）日：2016-10-27

  This invention provides novel indole, indazole, benzimidazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

  这项发明提供了新型吲哚、吲哚唑、苯并咪唑、吲哚啉、喹啉、异喹啉和咔唑选择性雄激素受体降解剂（SARD）化合物，以及在治疗前列腺癌、晚期前列腺癌、去势抵抗性前列腺癌、雄激素性脱发或其他高雄激素皮肤疾病、肯尼迪病、肌萎缩侧索硬化（ALS）和子宫肌瘤方面的药物组合物和用途，以及用于降低受试者体内雄激素受体全长（AR-FL）包括病原性和/或耐药突变、AR剪接变体（AR-SV）和AR病原性多谷氨酸（polyQ）多态性的水平的方法。
• Selective androgen receptor degrader (SARD) ligands and methods of use thereof
  申请人：GTx, Inc.

  公开号：US10017471B2

  公开（公告）日：2018-07-10

  This invention provides novel indole, indazole, benzimidazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, other AR-expressing cancers, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels (through degradation) and/or activity (through inhibition) of any androgen receptor including androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

  本发明提供了新型吲哚、吲唑、苯并咪唑、吲哚啉、喹诺酮、异喹啉和咔唑选择性雄激素受体降解剂（SARD）化合物、药物组合物及其在治疗前列腺癌、晚期前列腺癌、阉割耐药前列腺癌、其他表达AR的癌症、雄激素性脱发或其他高雄激素性皮肤病、肯尼迪病、肌萎缩性脊髓侧索硬化症（ALS）、腹主动脉瘤（AAA）和子宫肌瘤中的用途，以及降低其水平（通过降解）的方法、肌萎缩性脊髓侧索硬化症（ALS）、腹主动脉瘤（AAA）和子宫肌瘤，以及降低受试者体内任何雄激素受体的水平（通过降解）和/或活性（通过抑制）的方法，包括雄激素受体全长（AR-FL），包括致病性和/或抗性突变、AR-剪接变体（AR-SV）和致病性多谷氨酰胺（polyQ）多态性。
• Selective androgen receptor degrader (SARD) Ligands and methods of use thereof
  申请人：GTx, Inc.

  公开号：US10441570B2

  公开（公告）日：2019-10-15

  This invention provides novel indole, indazole, benzimidazole, benzotriazole, indoline, quinolone, isoquinoline, and carbazole selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating hyperproliferations of the prostate including pre-malignancies and benign prostatic hyperplasia, prostate cancer, advanced prostate cancer, castration resistant prostate cancer, other AR-expressing cancers, androgenic alopecia or other hyper androgenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels (through degradation) and/or activity (through inhibition) of any androgen receptor including androgen receptor-full length (AR-FL) including pathogenic and/or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.

  本发明提供了新型吲哚、吲唑、苯并咪唑、苯并三唑、吲哚啉、喹诺酮、异喹啉和咔唑选择性雄激素受体降解剂（SARD）化合物、药物组合物及其在治疗前列腺过度增生（包括恶性肿瘤前期和良性前列腺增生）、前列腺癌、晚期前列腺癌、阉割抵抗性前列腺癌、其他AR表达癌症中的用途、雄激素性脱发或其他高雄激素性皮肤病、肯尼迪病、肌萎缩性脊髓侧索硬化症（ALS）、腹主动脉瘤（AAA）和子宫肌瘤、以及降低受试者体内包括雄激素受体全长（AR-FL）在内的任何雄激素受体的水平（通过降解）和/或活性（通过抑制）的方法，包括致病性和/或抗性突变、AR-剪接变体（AR-SV）和致病性多聚谷氨酰胺（polyQ）多态性。
• SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF
  申请人：Gtx, Inc.

  公开号：EP3286164A1

  公开（公告）日：2018-02-28
• SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE
  申请人：University of Tennessee Research Foundation

  公开号：US20210161864A1

  公开（公告）日：2021-06-03

  This invention is directed to selective androgen receptor degrader (SARD) compounds pharmaceutical compositions and uses thereof in treating early prostate cancer, prostate cancer, advanced prostate cancer, castration resistant prostate cancer, triple negative breast cancer, other cancers expressing the androgen receptor, androgenic alopecia or other hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.