tert-butyl 4-[2-(thiophen-2-yl)quinazolin-4-yl]piperazine-1-carboxylate | 1222768-61-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: tert-butyl 4-[2-(thiophen-2-yl)quinazolin-4-yl]piperazine-1-carboxylate
• 英文别名: tert-butyl 4-(2-thiophen-2-ylquinazolin-4-yl)piperazine-1-carboxylate
• CAS: 1222768-61-7
• 化学式: C₂₁H₂₄N₄O₂S
• 分子量: 396.513
• InChiKey: XBRORLDCTPTWRG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  86.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-[2-(thiophen-2-yl)quinazolin-4-yl]piperazine-1-carboxylate 在 盐酸 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 4-{4-[(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl]piperazin-1-yl}-2-(thiophen-2-yl)quinazoline
  参考文献：
  名称：

  Evaluation of Quinazoline Analogues as Glucocerebrosidase Inhibitors with Chaperone Activity

  摘要：

  Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

  DOI：

  10.1021/jm1008902
• 作为产物：
  描述：

  2-噻吩硼酸 、 tert-butyl 4-(2-chloroquinazolin-4-yl)piperazine-1-carboxylate 在 bis-triphenylphosphine-palladium(II) chloride 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 16.0h， 以65%的产率得到tert-butyl 4-[2-(thiophen-2-yl)quinazolin-4-yl]piperazine-1-carboxylate
  参考文献：
  名称：

  Evaluation of Quinazoline Analogues as Glucocerebrosidase Inhibitors with Chaperone Activity

  摘要：

  Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.

  DOI：

  10.1021/jm1008902

文献信息

• Evaluation of Quinazoline Analogues as Glucocerebrosidase Inhibitors with Chaperone Activity
  作者：Juan J. Marugan、Wei Zheng、Omid Motabar、Noel Southall、Ehud Goldin、Wendy Westbroek、Barbara K. Stubblefield、Ellen Sidransky、Ronald A. Aungst、Wendy A. Lea、Anton Simeonov、William Leister、Christopher P. Austin

  DOI：10.1021/jm1008902

  日期：2011.2.24

  Gaucher disease is a lysosomal storage disorder (LSD) caused by deficiency in the enzyme glucocerebrosidase (GC). Small molecule chaperones of protein folding and translocation have been proposed as a promising therapeutic approach to this LSD. Most small molecule chaperones described in the literature contain an iminosugar scaffold. Here we present the discovery and evaluation of a new series of GC inhibitors with a quinazoline core. We demonstrate that this series can improve the translocation of GC to the lysosome in patient-derived cells. To optimize this chemical series, systematic synthetic modifications were performed and the SAR was evaluated and compared using three different readouts of compound activity: enzymatic inhibition, enzyme thermostabilization, and lysosomal translocation of GC.