2-[1-(4-chlorobenzoyl)-5-methoxyindol-3-yl]-N-methylsulfonylacetamide | 1427214-83-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 2-[1-(4-chlorobenzoyl)-5-methoxyindol-3-yl]-N-methylsulfonylacetamide
• CAS: 1427214-83-2
• 化学式: C₁₉H₁₇ClN₂O₅S
• 分子量: 420.873
• InChiKey: TZPGWJUMNMQCEH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  103
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  甲基磺酰胺 、 indomethacin 在 溶剂黄146 作用下， 以 水 为溶剂， 反应 20.0h， 以36%的产率得到2-[1-(4-chlorobenzoyl)-5-methoxyindol-3-yl]-N-methylsulfonylacetamide
  参考文献：
  名称：

  Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer

  摘要：

  Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5 alpha-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3.NADP(+).2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.

  DOI：

  10.1021/jm3017656

文献信息

• INDOMETHACIN ANALOGS FOR THE TREATMENT OF CASTRATE-RESISTANT PROSTATE CANCER
  申请人：Vanderbilt University

  公开号：US20140371261A1

  公开（公告）日：2014-12-18

  Provided are compositions for inhibiting a biological activity of an aldoketo reductase family 1, member C3 (AKR1 C3) polypeptide. In some embodiments, the compositions are indomethacin derivatives that are AKR1 C3-specific inhibitors. Also provided are methods for producing disclosed indomethacin derivatives that substantially lack cyclooxygenase inhibitory activity but that have AKR1C3 inhibitory activity, methods for inhibiting AKR1C3 polypeptide biological activities, and methods for treating prostate tumors in subjects.

  提供了一些用于抑制醛酮还原酶家族1成员C3（AKR1 C3）多肽生物活性的组合物。在某些实施例中，这些组合物是AKR1 C3特异性抑制剂的吲哚美辛衍生物。还提供了制备所述吲哚美辛衍生物的方法，这些方法基本上缺乏环氧合酶抑制活性，但具有AKR1C3抑制活性，以及抑制AKR1C3多肽生物活性的方法和治疗受试者的前列腺肿瘤的方法。
• US9346803B2
  申请人：——

  公开号：US9346803B2

  公开（公告）日：2016-05-24
• US9895351B2
  申请人：——

  公开号：US9895351B2

  公开（公告）日：2018-02-20
• Development of Potent and Selective Indomethacin Analogues for the Inhibition of AKR1C3 (Type 5 17β-Hydroxysteroid Dehydrogenase/Prostaglandin F Synthase) in Castrate-Resistant Prostate Cancer
  作者：Andy J. Liedtke、Adegoke O. Adeniji、Mo Chen、Michael C. Byrns、Yi Jin、David W. Christianson、Lawrence J. Marnett、Trevor M. Penning

  DOI：10.1021/jm3017656

  日期：2013.3.28

  Castrate-resistant prostate cancer (CRPC) is a fatal, metastatic form of prostate cancer. CRPC is characterized by reactivation of the androgen axis due to changes in androgen receptor signaling and/or adaptive intratumoral androgen biosynthesis. AKR1C3 is upregulated in CRPC where it catalyzes the formation of potent androgens. This makes AKR1C3 a target for the treatment of CRPC. AKR1C3 inhibitors should not inhibit AKR1C1/AKR1C2, which inactivate 5 alpha-dihydrotestosterone. Indomethacin, used to inhibit cyclooxygenase, also inhibits AKR1C3 and displays selectivity over AKR1C1/AKR1C2. Parallel synthetic strategies were used to generate libraries of indomethacin analogues, which exhibit reduced cyclooxygenase inhibitory activity but retain AKR1C3 inhibitory potency and selectivity. The lead compounds inhibited AKR1C3 with nanomolar potency, displayed >100-fold selectivity over AKR1C1/AKR1C2, and blocked testosterone formation in LNCaP-AKR1C3 cells. The AKR1C3.NADP(+).2'-des-methyl-indomethacin crystal structure was determined, and it revealed a unique inhibitor binding mode. The compounds reported are promising agents for the development of therapeutics for CRPC.