AGN 195183 | 367273-07-2

• 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: AGN 195183
• 英文别名: IRX5183；4-(4-Chloro-3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene-2-carboxamido)-2,6-difluorobenzoic acid；4-[(4-chloro-3-hydroxy-5,5,8,8-tetramethyl-6,7-dihydronaphthalene-2-carbonyl)amino]-2,6-difluorobenzoic acid
• CAS: 367273-07-2
• 化学式: C₂₂H₂₂ClF₂NO₄
• 分子量: 437.871
• InChiKey: PNAWUIKCVQSLFG-UHFFFAOYSA-N

物化性质

• 沸点：
  500.9±50.0 °C(Predicted)
• 密度：
  1.354±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：≥ 62 mg/mL（141.60 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  86.6
• 氢给体数：
  3
• 氢受体数：
  6

制备方法与用途

生物活性方面，AGN 195183是一种选择性的RARα激动剂，其Kd值为3 nM，相较于AGN 193836具有更好的结合选择性，并且不对RARβ/γ产生活性。

反应信息

• 作为产物：
  描述：

  3-methoxy-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylic acid 在 吡啶 、 sodium hydroxide 、 氯化亚砜 、 三溴化硼 作用下， 以 乙醚 、 乙醇 、 二氯甲烷 为溶剂， 生成 AGN 195183
  参考文献：
  名称：

  Synthesis and biological activity of retinoic acid receptor-α specific amides

  摘要：

  Retinoids are analogues of all-trans-retinoic acid, a powerful hormone that mediates many fundamental biological processes. Cancer and other serious hyperprolifierative diseases are attractive therapeutic targets for retinoids, but the therapeutic use of retinoids is limited due to severe toxicity. We report here the design of retinoid receptor-alpha specific ligands with growth inhibitory activity in breast cancer cell lines, and which do not cause the cutaneous toxicity associated with the currently available nonselective retinoid agonists. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0960-894x(02)00647-9

文献信息

• Treatment of tumors with RARalpha selective retinoid compounds in combination with other anti-tumor agents
  申请人：Allergan Sales, Inc.

  公开号：US20010039293A1

  公开（公告）日：2001-11-08

  Compounds which are specific or selective agonists of RAR&agr; receptors in preference over RAR&bgr; and RAR&ggr; receptors, and particularly compounds of the formula 1 where R is a H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt, are useful for treating a malignant disease or condition in a mammal. In treatment of solid tumors the compound exhibit synergistic anti-proliferative effect with human recombinant interferon.

  具有特异性或选择性作用于RAR&agr;受体，而优先于RAR&bgr;和RAR&ggr;受体的化合物，尤其是公式1中R为H，1至6个碳的低烷基或药物可接受的盐的化合物，可用于治疗哺乳动物的恶性疾病或病况。在固体肿瘤的治疗中，该化合物与人重组干扰素表现出协同的抗增殖效应。
• Treatment of tumors with RAR alpha selective retinoid compounds in combination with other anti-tumor agents
  申请人：ALLERGAN, INC.

  公开号：EP1650188A1

  公开（公告）日：2006-04-26

  Compounds which are specific or selective agonists of RARα receptors in preference over RARβ and RARγ receptors, and particularly compounds of the formula (I) where R is a H, lower alkyl of 1 to 6 carbons, or a pharmaceutically acceptable salt, are useful for treating a malignant disease or condition in a mammal. In treatment of solid tumors the compound exhibit synergistic antiproliferative effect with human recombinant interferon.

  与 RARβ 和 RARγ 受体相比，作为 RARα 受体的特异性或选择性激动剂的化合物，尤其是式 (I) 中 R 为 H、1-6 碳原子的低级烷基或药学上可接受的盐的化合物，可用于治疗哺乳动物的恶性疾病或病症。在治疗实体瘤时，该化合物与人重组干扰素具有协同抗增殖作用。
• USE OF CYP26-RESISTANT RAR ALPHA SELECTIVE AGONISTS IN THE TREATMENT OF CANCER
  申请人：IO Therapeutics, Inc.

  公开号：EP3957304A1

  公开（公告）日：2022-02-23

  Disclosed herein are methods for treating a cancer comprising administering to a subject in need thereof an effective dose of a CYP26-resistant retinoic acid receptor (RAR) alpha (RARα) selective agonist, whereby as a result of the treatment the tumor burden is reduced in the subject and cancer stem cells resident in the bone marrow are substantially reduced.

  本文公开了治疗癌症的方法，包括向有需要的受试者施用有效剂量的抗CYP26维甲酸受体（RAR）α（RARα）选择性激动剂，治疗的结果是减轻受试者的肿瘤负担，并大大减少骨髓中的癌症干细胞。
• Methods of stratifying patients for treatment with retinoic acid receptor-alpha agonists
  申请人：Syros Pharmaceuticals, Inc.

  公开号：US10167518B2

  公开（公告）日：2019-01-01

  The invention provides methods that define cellular populations that are sensitive to RARA agonists and identify patient subgroups that will benefit from treatment with RARA agonists. The invention also provides packaged pharmaceutical compositions that comprise a RARA agonist and instructions for determining if such agonist is suitable for use in treatment.

  本发明提供的方法可确定对 RARA 激动剂敏感的细胞群，并识别将从 RARA 激动剂治疗中获益的患者亚群。本发明还提供了包含 RARA 激动剂的包装药物组合物，以及确定这种激动剂是否适合用于治疗的说明。
• RAR selective agonists in combination with immune modulators for cancer immunotherapy
  申请人：Io Therapeutics, Inc.

  公开号：US10363272B2

  公开（公告）日：2019-07-30

  Disclosed herein are methods for treating cancer comprising administering CAR-modified immune cells and at least one Retinoic Acid Receptor agonist.

  本文公开了治疗癌症的方法，包括给药 CAR 修饰的免疫细胞和至少一种视黄酸受体激动剂。