2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol | 1126084-35-2

• 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-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol
• 英文别名: [4-(2-hydroxy-2-methylpropyl)piperidin-1-yl]-(5-methyl-1H-indol-2-yl)methanone
• CAS: 1126084-35-2
• 化学式: C₁₉H₂₆N₂O₂
• 分子量: 314.428
• InChiKey: QGUMEWLTIYRZFH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 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：

  benzyl 4-(2-hydroxy-2-methylpropyl)piperidine-1-carboxylate 在 palladium 10% on activated carbon 、 氢气 、 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 、 甲醇 、 水 为溶剂， 反应 24.0h， 生成 2-methyl-1-{1-[(5-methyl-1H-indol-2-yl)carbonyl]piperidin-4-yl}propan-2-ol
  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

• Piperidine derivative
  申请人：Kakefuda Akio

  公开号：US08513422B2

  公开（公告）日：2013-08-20

  As a result of studies on compounds having a selective inhibitory activity against 17βHSD type 5, the present inventors have confirmed that a 1-[(indol-2-yl)carbonyl]piperidyl}alkanol derivative has a potent selective inhibitory activity against 17βHSD type 5. The invention has been completed based on these findings. The compound of the present invention can be used as an agent for treating and/or an agent for preventing diseases associated with 17βHSD type 5, such as benign prostatic hyperplasia and prostate cancer, without accompanying adverse effects due to a decrease in testosterone.

  通过对具有选择性抑制17βHSD型5活性的化合物的研究，本发明人已经确认一种1-[(indol-2-yl)carbonyl]piperidyl}alkanol衍生物具有强大的选择性抑制17βHSD型5的活性。本发明基于这些发现已经完成。本发明的化合物可用作治疗和/或预防与17βHSD型5相关的疾病的药物，如良性前列腺增生和前列腺癌，而不伴随着由于睾酮降低而引起的不良反应。
• PIPERIDINE DERIVATIVE
  申请人：Astellas Pharma Inc.

  公开号：EP2181990B1

  公开（公告）日：2012-08-08
• US8513422B2
  申请人：——

  公开号：US8513422B2

  公开（公告）日：2013-08-20
• 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.