(S)-3-(3-chloro-5-fluoro-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-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)-3-(3-chloro-5-fluoro-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide
• 英文别名: (2S)-3-(3-chloro-5-fluoroindol-1-yl)-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide
• 化学式: C₂₀H₁₄ClF₄N₃O₂
• 分子量: 439.797
• InChiKey: VQPCUPSWQUHUJV-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 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 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 3.83h， 生成 (S)-3-(3-chloro-5-fluoro-1H-indol-1-yl)-N-(4-cyano-3-(trifluoromethyl)phenyl)-2-hydroxy-2-methylpropanamide
  参考文献：
  名称：

  WO2019222556A5

  摘要：

  公开号：

  WO2019222556A5

文献信息

• Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer
  作者：Dong-Jin Hwang、Yali He、Suriyan Ponnusamy、Thirumagal Thiyagarajan、Michael L. Mohler、Ramesh Narayanan、Duane D. Miller

  DOI：10.1021/acs.jmedchem.2c01858

  日期：2023.3.9

  while retaining potent antagonistic activity for an AR. This structure–activity relationship (SAR) study of more than 50 compounds classified with three classes (Class I, II, and III) and discovered two compounds (32c and 35i) that are potent AR antagonists (e.g., IC50 = 0.021 μM, T1/2 = 120 min for compound 35i). The new antagonists exhibited improved in vivo pharmacokinetics (PK) with high efficacy antiandrogen

  雄激素受体（AR）拮抗剂领域新药发现的一个主要挑战在于预测可成药特性，这些特性将使小分子在体外和体内的进一步研究中保持其效力和稳定性。Indole（化合物8）是一种一流的 AR 拮抗剂，具有非常高的效力 (IC 50 = 0.085 μM)，但代谢不稳定。在本文描述的代谢研究中，我们合成了新的小分子，其稳定性显着提高，同时保留了对 AR 的有效拮抗活性。这项构效关系 (SAR) 研究将 50 多种化合物分为三类（I、II 和 III 类），并发现了两种化合物（32c 和35i）是有效的 AR 拮抗剂（例如，IC 50 = 0.021 μM，对于化合物35i ， T 1/2 = 120 分钟）。新拮抗剂在过表达 AR (LNCaP-AR) 的 Hershberger 和抗雄激素 Enz-Res 肿瘤异种移植模型中表现出改善的体内药代动力学 (PK) 和高效抗雄激素活性。
• 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：University of Tennessee Research Foundation

  公开号：US10806720B2

  公开（公告）日：2020-10-20

  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.

  本发明涉及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早期前列腺癌、前列腺癌、晚期前列腺癌、对阉割有抵抗力的前列腺癌、三阴性乳腺癌、其他表达雄激素受体的癌症、雄激素性脱发或其他高雄激素性皮肤病中的用途、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雄激素受体全长（AR-FL）水平的方法，包括致病性或抗性突变、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：EP3793541A1

  公开（公告）日：2021-03-24
• 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.