N-{trans-3-[(5-cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-{trans-3-[(5-cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide
• 英文别名: N-[3-(5-cyano-6-methylpyridin-2-yl)oxy-2,2,4,4-tetramethylcyclobutyl]-6-methoxyimidazo[1,2-b]pyridazine-3-carboxamide
• 化学式: C₂₃H₂₆N₆O₃
• 分子量: 434.498
• InChiKey: ACOVBETWSRFEDO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  114
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  6-fluoro-2-methyl-3-cyanopyridine 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-[(5-cyano-6-methylpyridin-2-yl)oxy]-2,2,4,4-tetramethylcyclobutyl}-6-methoxyimidazo[1,2-b]pyridazine-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