(S)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-methyl-2-(pyridin-3-yl)guinazolin-4-amine

• 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: (S)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-methyl-2-(pyridin-3-yl)guinazolin-4-amine
• 英文别名: (S)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine；Gcase activator 3；N-[[(3S)-2,3-dihydro-1,4-benzodioxin-3-yl]methyl]-N-methyl-2-pyridin-3-ylquinazolin-4-amine
• 化学式: C₂₃H₂₀N₄O₂
• 分子量: 384.437
• InChiKey: JFOVNJQCUHRYOI-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  60.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氨基苯甲腈 在 环丁砜 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (S)-N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-methyl-2-(pyridin-3-yl)guinazolin-4-amine
  参考文献：
  名称：

  将喹唑啉调节剂从抑制剂转变为β-葡萄糖脑苷脂酶的活化剂。

  摘要：

  高雪氏病是一种溶酶体病，是由β-葡萄糖脑苷脂酶基因（GBA1和GCase）的突变引起的，这些突变也与帕金森氏病（PD）和弥漫性路易氏体痴呆的风险增加有关。先前的研究表明，突变的GCase蛋白会发生错误折叠和降解，因此，突变蛋白的稳定代表了突触核蛋白病的重要治疗策略。在这项工作中，我们提出了作为GCase抑制剂的喹唑啉化合物的构效关系（SAR）研究。出乎意料的是，我们发现这些抑制剂的N-甲基化将它们转化为GCase激活剂。一项系统的SAR研究进一步表明，替换喹唑啉衍生物连接基中的关键氧原子也有助于活性转换。PD患者衍生的成纤维细胞和多巴胺能中脑神经元用选定的化合物（9q）处理，该化合物部分稳定了GCase并提高了其活性。这些结果突出了PD和相关突触核蛋白病中非抑制性GCase调节剂的治疗性开发的新策略。

  DOI：

  10.1021/acs.jmedchem.8b01294

文献信息

• [EN] SUBSTITUTED FUSED PYRIMIDINE COMPOUNDS AND USES THERE<br/>[FR] COMPOSÉS DE PYRIMIDINE FUSIONNÉS SUBSTITUÉS ET LEURS UTILISATIONS
  申请人：UNIV NORTHWESTERN

  公开号：WO2019027765A1

  公开（公告）日：2019-02-07

  Disclosed are new small molecules having a substituted pyrimidine or substituted fused pyrimidine core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules which may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including Gaucher' s disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. The small molecules may contain a fluorophore or may be conjugated to a fluorophore in order to prepare a fluorescent probe for use in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.

  揭示了具有取代嘧啶或取代融合嘧啶核结构的新型小分子及其用途，用于调节葡萄糖鞘苷酶活性。还公开了包含这些小分子的药物组合物，可用于治疗与葡萄糖鞘苷酶活性相关的疾病或疾病，包括高雪氏病和神经系统疾病和障碍，如遗传性和散发性突触核蛋白病，包括帕金森病、带有莱维小体的痴呆症和与异常葡萄糖鞘苷酶活性相关的多系统萎缩。这些小分子可能含有荧光团或与荧光团结合，以制备用于高通量筛选方法中识别通过荧光极化调节葡萄糖鞘苷酶活性的新调节剂的荧光探针。
• SUBSTITUTED FUSED PYRIMIDINE COMPOUNDS AND USES THEREOF
  申请人：Northwestern University

  公开号：US20200283444A1

  公开（公告）日：2020-09-10

  Disclosed are new small molecules having a substituted pyrimidine or substituted fused pyrimidine core structure and the uses thereof for modulating glucocerebrosidase activity. Also disclosed are pharmaceutical compositions comprising the small molecules which may be administered in methods of treating diseases or disorders associated with glucocerebrosidase activity, including Gaucher's disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. The small molecules may contain a fluorophore or may be conjugated to a fluorophore in order to prepare a fluorescent probe for use in high throughput screening methods to identify new modulators of glucocerebrosidase activity via fluorescence polarization.