(S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-1H-pyrazol-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-(3-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide
• 英文别名: (2S)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-(3-fluoropyrazol-1-yl)-2-hydroxy-2-methylpropanamide
• 化学式: C₁₅H₁₂F₄N₄O₂
• 分子量: 356.279
• InChiKey: VPINQEFVSVMLJX-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  90.9
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  (2R)-3-bromo-N-[4-cyano-3-(trifluoromethyl)phenyl]-2-hydroxy-2-methylpropanamide 在 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 丁酮 、 mineral oil 为溶剂， 反应 5.0h， 生成 (S)-N-(4-cyano-3-(trifluoromethyl)phenyl)-3-(3-fluoro-1H-pyrazol-1-yl)-2-hydroxy-2-methylpropanamide
  参考文献：
  名称：

  吡唑-1-基-丙酰胺作为 SARD 和泛拮抗剂治疗恩杂鲁胺耐药的前列腺癌

  摘要：

  我们在此报告了作为选择性雄激素受体降解剂 (SARDs) 和泛拮抗剂的新型芳基吡唑-1-基-丙酰胺库的设计、合成和药理学表征，它们具有广泛的 AR 拮抗作用。药理学评估表明，在常见的 A 环-连接-B 环非甾体类抗雄激素的一般药效团中引入吡唑部分作为 B 环结构元件，允许开发具有独特 SARD 和泛拮抗剂活性的新小分子支架甚至与我们最近发布的 AF-1 结合 SARD 相比，例如 UT-155 ( 9 ) 和 UT-34 ( 10）。新型 B 环吡唑表现出有效的 AR 拮抗剂活性，包括有希望的分布、代谢和药代动力学特性，以及广谱 AR 拮抗剂特性，包括有效的体内抗肿瘤活性。26a能够对源自恩杂鲁胺抗性 (Enz-R) VCaP 细胞系的异种移植物诱导 80% 的肿瘤生长抑制。这些结果代表了开发用于治疗 Enz-R 前列腺癌的新型 AR 拮抗剂的进展。

  DOI：

  10.1021/acs.jmedchem.0c00943

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 DE RÉCEPTEURS DES ANDROGÈNES - ET MÉTHODES D'UTILISATION
  申请人：UNIV TENNESSEE RES FOUND

  公开号：WO2017214634A1

  公开（公告）日：2017-12-14

  This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including heterocyclic anilide rings and their synthetic precursors, R-isomers, and non-hydroxylated and/or non-chiral propanamides, and pharmaceutical compositions and uses thereof in treating 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.

  该发明涉及吡咯、吡唑、咪唑、三唑和吗啉基选择性雄激素受体降解剂（SARD）化合物，包括含有杂环苯胺环的合成前体、R-异构体以及非羟基化和/或非手性的丙酰胺，以及在治疗前列腺癌、晚期前列腺癌、去势耐药性前列腺癌、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皮肤疾病、肯尼迪病、肌萎缩性侧索硬化（ALS）、腹主动脉瘤和子宫肌瘤等方面的制药组合物和用途，以及用于降低受试者中雄激素受体全长（AR-FL）的水平，包括致病性或耐药突变、AR-剪接变体（AR-SV）和AR的致病性多谷氨酸（polyQ）多态性的方法。
• Selective androgen receptor degrader (SARD) ligands and methods of use thereof
  申请人：University of Tennessee Research Foundation

  公开号：US10314797B2

  公开（公告）日：2019-06-11

  This invention is directed to pyrrole, pyrazole, imidazole, triazole, and morpholine based selective androgen receptor degrader (SARD) compounds including heterocyclic anilide rings and their synthetic precursors, R-isomers, and non-hydroxylated and/or non-chiral propanamides, and pharmaceutical compositions and uses thereof in treating 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.

  本发明涉及吡咯、吡唑、咪唑、三唑和吗啉基选择性雄激素受体降解剂（SARD）化合物，包括杂环苯胺环及其合成前体、R-异构体和非羟基化和/或非手性丙酰胺，以及治疗前列腺癌、晚期前列腺癌、阉割耐药前列腺癌、三阴性乳腺癌的药物组合物及其用途、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、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）和致病性多谷氨酰胺（polyQ）AR多态性。
• [EN] PYRAZOLYLPROPANAMIDE COMPOUNDS AND USES THEREOF FOR TREATMENT OF PROSTATE CANCER<br/>[FR] COMPOSÉS DE PYRAZOLYLPROPANAMIDE ET LEURS UTILISATIONS POUR LE TRAITEMENT DU CANCER DE LA PROSTATE
  申请人：UNIV TENNESSEE RES FOUND

  公开号：WO2021202936A9

  公开（公告）日：2022-01-06
• SELECTIVE ANDROGEN RECEPTOR DEGRADER (SARD) LIGANDS AND METHODS OF USE THEREOF
  申请人：University of Tennessee Research Foundation

  公开号：EP3976577A1

  公开（公告）日：2022-04-06
• 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.