N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]imidazo[1,2-a]pyrimidine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]imidazo[1,2-a]pyrimidine-3-carboxamide
• 英文别名: N-((1r,3r)-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl)imidazo[1,2-a]pyrimidine-3-carboxamide；N-[3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]imidazo[1,2-a]pyrimidine-3-carboxamide
• 化学式: C₂₂H₂₂ClN₅O₂
• 分子量: 423.902
• InChiKey: BPBNRBPFAJMRAQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  92.3
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-氯-4-氟苯腈 在 盐酸 、 sodium hydride 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 N-[trans-3-(3-chloro-4-cyanophenoxy)-2,2,4,4-tetramethylcyclobutyl]imidazo[1,2-a]pyrimidine-3-carboxamide
  参考文献：
  名称：

  Systematic Structure Modifications of Imidazo[1,2-a]pyrimidine to Reduce Metabolism Mediated by Aldehyde Oxidase (AO)

  摘要：

  N-{trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy] 2,2,4,4-tetramethylcyclobutyl}imidazo [1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.

  DOI：

  10.1021/jm2010942

文献信息

• Discovery of Aryloxy Tetramethylcyclobutanes as Novel Androgen Receptor Antagonists
  作者：Chuangxing Guo、Angelica Linton、Susan Kephart、Martha Ornelas、Mason Pairish、Javier Gonzalez、Samantha Greasley、Asako Nagata、Benjamin J. Burke、Martin Edwards、Natilie Hosea、Ping Kang、Wenyue Hu、Jon Engebretsen、David Briere、Manli Shi、Hovik Gukasyan、Paul Richardson、Kevin Dack、Toby Underwood、Patrick Johnson、Andrew Morell、Robert Felstead、Hidetoshi Kuruma、Hiroaki Matsimoto、Amina Zoubeidi、Martin Gleave、Gerrit Los、Andrea N. Fanjul

  DOI：10.1021/jm201059s

  日期：2011.11.10

  An aryloxy tetramethylcyclobutane was identified as a novel template for androgen receptor (AR) antagonists via cell-based high-throughput screening. Follow-up to the initial "hit" established 5 as a viable lead. Further optimization to achieve full AR antagonism led to the discovery of 26 and 30, both of which demonstrated excellent in vivo tumor growth inhibition upon oral administration in a castration-resistant prostate cancer (CRPC) animal model.
• Systematic Structure Modifications of Imidazo[1,2-<i>a</i>]pyrimidine to Reduce Metabolism Mediated by Aldehyde Oxidase (AO)
  作者：Angelica Linton、Ping Kang、Martha Ornelas、Susan Kephart、Qiyue Hu、Mason Pairish、Ying Jiang、Chuangxing Guo

  DOI：10.1021/jm2010942

  日期：2011.11.10

  N-trans-3-[(5-Cyano-6-methylpyridin-2-yl)oxy] 2,2,4,4-tetramethylcyclobutyl}imidazo [1,2-a]pyrimidine-3-carboxamide (1) was recently identified as a full antagonist of the androgen receptor, demonstrating excellent in vivo tumor growth inhibition in castration-resistant prostate cancer (CRPC). However, the imidazo[1,2-a]pyrimidine moiety is rapidly metabolized by aldehyde oxidase (AO). The present paper describes a number of medicinal chemistry strategies taken to avoid the AO-mediated oxidation of this particular system. Guided by an AO protein structure-based model, our investigation revealed the most probable site of AO oxidation and the observation that altering the heterocycle or blocking the reactive site are two of the more effective strategies for reducing AO metabolism. These strategies may be useful for other drug discovery programs.