3-((4-(三氟甲基)苯基)氨基)苯甲酸 | 1284180-11-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 3-((4-(三氟甲基)苯基)氨基)苯甲酸
• 英文名称: 3-[N-(4-trifluoromethylphenyl)amino]benzoic acid
• 英文别名: 3-((4-trifluoromethyl)phenylamino)benzoic acid；3-((4-(Trifluoromethyl)Phenyl)Amino)Benzoic Acid；3-[4-(trifluoromethyl)anilino]benzoic acid
• CAS: 1284180-11-5
• 化学式: C₁₄H₁₀F₃NO₂
• 分子量: 281.234
• InChiKey: MDZIRNPRVJEHHX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  3-[N-(4-trifluoromethylphenyl)amino]benzoic acid methyl ester 在 potassium hydroxide 、 盐酸 作用下， 以 乙醇 、 水 为溶剂， 以90%的产率得到3-((4-(三氟甲基)苯基)氨基)苯甲酸
  参考文献：
  名称：

  Development of Potent and Selective Inhibitors of Aldo–Keto Reductase 1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase) Based on N-Phenyl-Aminobenzoates and Their Structure–Activity Relationships

  摘要：

  Aldo-keto reductase 1C3 (AKR1C3; type 5 17 beta-hydroxysteroid dehydrogenase) is overexpressed in castration resistant prostate cancer (CRPC) and is implicated in the intratumoral biosynthesis of testosterone and 5 alpha-dihydrotestosterone. Selective AKR1C3 inhibitors are required because compounds should not inhibit the highly related AKR1C1 and AKR1C2 isoforms which are involved in the inactivation of Sa-dihydrotestosterone. NSAIDs, N-phenylanthranilates in particular, are potent but nonselective AKR1C3 inhibitors. Using flufenamic acid, 2-{[3-(trifluoromethyl)phenyl]amino}benzoic acid, as lead compound, five classes of structural analogues were synthesized and evaluated for AKR1C3 inhibitory potency and selectivity. Structure-activity relationship (SAR) studies revealed that a meta-carboxylic acid group relative to the amine conferred pronounced AKR1C3 selectivity without loss of potency, while electron withdrawing groups on the phenylamino B-ring were optimal for AKR1C3 inhibition. Lead compounds did not inhibit COX-1 or COX-2 but blocked the AKR1C3 mediated production of testosterone in LNCaP-AKR1C3 cells. These compounds offer promising leads toward new therapeutics for CRPC.

  DOI：

  10.1021/jm201547v

文献信息

• ALDO-KETO REDUCTASE SUBFAMILY 1C3 (AKR1C3) INHIBITORS
  申请人：DALTON James T.

  公开号：US20130116277A1

  公开（公告）日：2013-05-09

  The present invention relates to a novel class of AKR1C3 inhibitors, to compositions containing them, to methods for their preparation, and to methods of use thereof. The AKR1C3 inhibitors may be useful in the treatment of, for example, prostate cancer, benign prostate hyperplasia (BPH), lung cancer, acne, seborrhea, hirsuitism, baldness, alopecia, precocious puberty, adrenal hypertrophy, polycystic ovary syndrome, breast cancer, uterine cancer, uterine fibroids, endometriosis, myeloma and leiomyoma.

  本发明涉及一种新型AKR1C3抑制剂类，包含其组成物，其制备方法以及使用方法。这些AKR1C3抑制剂可能在治疗前列腺癌、良性前列腺增生症（BPH）、肺癌、痤疮、皮脂溢出、多毛症、脱发、斑秃、性早熟、肾上腺增生、多囊卵巢综合症、乳腺癌、子宫癌、子宫肌瘤、子宫内膜异位症、骨髓瘤和平滑肌瘤的治疗中有用。
• Bifunctional AKR1C3 Inhibitors/Androgen Receptor Modulators and Methods of Use Thereof
  申请人：The Trustees of The University of Pennsylvania

  公开号：US20140107085A1

  公开（公告）日：2014-04-17

  The invention includes compositions comprising selective AKR1C3 inhibitors. The invention also includes compositions comprising bifunctional AKR1C3 inhibitors and selective androgen receptor modulators. The invention further includes methods of treatment using the compositions of the invention.

  该发明包括含有选择性AKR1C3抑制剂的组合物。该发明还包括含有双功能AKR1C3抑制剂和选择性雄激素受体调节剂的组合物。该发明还包括使用该发明的组合物进行治疗的方法。
• Bifunctional AKR1C3 inhibitors/androgen receptor modulators and methods of use thereof
  申请人：The Trustees of the University of Pennsylvania

  公开号：US10071953B2

  公开（公告）日：2018-09-11

  The invention includes compositions comprising selective AKR1C3 inhibitors. The invention also includes compositions comprising bifunctional AKR1C3 inhibitors and selective androgen receptor modulators. The invention further includes methods of treatment using the compositions of the invention.

  本发明包括由选择性 AKR1C3 抑制剂组成的组合物。本发明还包括包含双功能 AKR1C3 抑制剂和选择性雄激素受体调节剂的组合物。本发明还包括使用本发明组合物的治疗方法。
• Treatment of metastatic prostate cancer
  申请人：The Regents of the University of California

  公开号：US11215617B2

  公开（公告）日：2022-01-04

  The present invention provides new compositions and methods for treating prostate cancer, e.g., drug-resistant prostate cancer, such as anti-androgen drug (e.g., enzalutamide) resistant and/or castration resistant prostate cancer (CRPC). These new compositions include, but are not limited to, pharmaceutical compositions that include an AR-V7 inhibitor, such as niclosamide. Alternatively, these new compositions can include, but are not limited to, pharmaceutical compositions that include an AKR1C3 inhibitor, such as indomethacin. These new methods include, but are not limited to, methods of administering an AR-V7 inhibitor, such as niclosamide, and/or an AKR1C3 inhibitor, such as indomethacin, to treat patients having prostate cancer. The present invention also provides methods of inhibiting androgen receptor variant expression, e.g. AR-V7, and methods of killing cells expressing AR-V7. The present invention further provides methods of inhibiting AKR1C3 expression or activity, and methods of killing cells that express AKR1C3.

  本发明提供了治疗前列腺癌，例如耐药前列腺癌，如抗雄激素药物（如恩扎鲁胺）耐药和/或阉割耐药前列腺癌（CRPC）的新组合物和方法。这些新组合物包括但不限于包括AR-V7抑制剂如尼可刹米的药物组合物。或者，这些新组合物可以包括但不限于包括AKR1C3抑制剂（如吲哚美辛）的药物组合物。这些新方法包括但不限于施用AR-V7抑制剂如尼可刹米和/或AKR1C3抑制剂如吲哚美辛治疗前列腺癌患者的方法。本发明还提供了抑制雄激素受体变体（如 AR-V7）表达的方法，以及杀死表达 AR-V7 的细胞的方法。本发明进一步提供了抑制AKR1C3表达或活性的方法，以及杀死表达AKR1C3的细胞的方法。
• Discovery of substituted 3-(phenylamino)benzoic acids as potent and selective inhibitors of type 5 17β-hydroxysteroid dehydrogenase (AKR1C3)
  作者：Adegoke O. Adeniji、Barry M. Twenter、Michael C. Byrns、Yi Jin、Jeffrey D. Winkler、Trevor M. Penning

  DOI：10.1016/j.bmcl.2011.01.010

  日期：2011.3

  Aldo-keto reductase 1C3 (AKR1C3) also known as type 5 17 beta-hydroxysteroid dehydrogenase has been implicated as one of the key enzymes driving the elevated intratumoral androgen levels observed in castrate resistant prostate cancer (CRPC). AKR1C3 inhibition therefore presents a rational approach to managing CRPC. Inhibitors should be selective for AKR1C3 over other AKR1C enzymes involved in androgen metabolism. We have synthesized 2-, 3-, and 4-(phenylamino)benzoic acids and identified 3-(phenylamino) benzoic acids that have nanomolar affinity and exhibit over 200-fold selectivity for AKR1C3 versus other AKR1C isoforms. The AKR1C3 inhibitory potency of the 4'-substituted 3-(phenylamino)benzoic acids shows a linear correlation with both electronic effects of substituents and the pK(a) of the carboxylic acid and secondary amine groups, which are interdependent. These compounds may be useful in treatment and/or prevention of CRPC as well as understanding the role of AKR1C3 in endocrinology. (C) 2011 Elsevier Ltd. All rights reserved.