3-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propanol | 1242427-70-8

• 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: 3-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propanol
• 英文别名: [4-(3-hydroxypropyl)piperidin-1-yl]-(5-methyl-1H-indol-2-yl)methanone
• CAS: 1242427-70-8
• 化学式: C₁₈H₂₄N₂O₂
• 分子量: 300.401
• InChiKey: VVRGZXPEEBHJPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  56.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  3-(4-哌啶基)-1-丙醇 、 5-甲基吲哚-2-甲酸 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 为溶剂， 以73%的产率得到3-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propanol
  参考文献：
  名称：

  Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol: A novel, potent and selective type 5 17β-hydroxysteroid dehydrogenase inhibitor

  摘要：

  Type 5 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD5), also known as aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily of enzymes and is expressed in the human prostate. One of the main functions of 17 beta-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5 alpha-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17 beta-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17 beta-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (FITS) and identified compound 2, which displayed a structure distinct from known 17 beta-HSD5 inhibitors. To optimize the inhibitory activity of compound 2, we first introduced a primary alcohol group. We then converted the primary alcohol group to a tertiary alcohol, which further enhanced the inhibitory activity, improved metabolic stability, and led to the identification of compound 17. Oral administration of compound 17 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione (AD)-induced intratumoral testosterone production. Compound 17 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and enhanced pharmacokinetic and physicochemical properties. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.06.025

文献信息

• [EN] INDOLE COMPOUND<br/>[FR] COMPOSÉ INDOLE
  申请人：ASTELLAS PHARMA INC

  公开号：WO2010101127A1

  公开（公告）日：2010-09-10

  【課題】本発明の課題は、医薬組成物、例えば１７βＨＳＤ　ｔｙｐｅ　５の関与する疾患の治療剤として有用な化合物の提供である。 【解決手段】本発明者らは、１７βＨＳＤ　ｔｙｐｅ　５の関与する疾患の治療剤として有用な化合物について鋭意検討した結果、２位に置換カルバモイル基を有するインドール化合物が、強力な１７βＨＳＤ　ｔｙｐｅ　５阻害活性を有すること、並びに、テストステロン減少による副作用を伴わない、前立腺肥大症及び前立腺癌等の１７βＨＳＤ　ｔｙｐｅ　５の関与する疾患の治療剤及び／又は予防剤となりうることを知見して本発明を完成した。
• Discovery of 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol: A novel, potent and selective type 5 17β-hydroxysteroid dehydrogenase inhibitor
  作者：Kazushi Watanabe、Akio Kakefuda、Minoru Yasuda、Kentaro Enjo、Aya Kikuchi、Takashi Furutani、Yoichi Naritomi、Yukio Otsuka、Minoru Okada、Mitsuaki Ohta

  DOI：10.1016/j.bmc.2013.06.025

  日期：2013.9

  Type 5 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD5), also known as aldo-keto reductase 1C3 (AKR1C3), is a member of the aldo-keto reductase superfamily of enzymes and is expressed in the human prostate. One of the main functions of 17 beta-HSD5 is to catalyze the conversion of the weak androgen, androstenedione, to the potent androgen, testosterone. The concentration of intraprostatic 5 alpha-dihydrotestosterone (DHT) in patients following chemical or surgical castration has been reported to remain as high as 39% of that of healthy men, with 17 beta-HSD5 shown to be involved in this androgen synthesis. Inhibition of 17 beta-HSD5 therefore represents a promising target for the treatment of castration-resistant prostate cancer (CRPC). To investigate this, we conducted high-throughput screening (FITS) and identified compound 2, which displayed a structure distinct from known 17 beta-HSD5 inhibitors. To optimize the inhibitory activity of compound 2, we first introduced a primary alcohol group. We then converted the primary alcohol group to a tertiary alcohol, which further enhanced the inhibitory activity, improved metabolic stability, and led to the identification of compound 17. Oral administration of compound 17 to castrated nude mice bearing the CWR22R xenograft resulted in the suppression of androstenedione (AD)-induced intratumoral testosterone production. Compound 17 also demonstrated good isoform selectivity, minimal inhibitory activity against either CYP or hERG, and enhanced pharmacokinetic and physicochemical properties. (C) 2013 Elsevier Ltd. All rights reserved.