5-(4-(4-acetylphenyl)piperazine-1-carbonyl)indolin-2-one | 1374752-85-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 5-(4-(4-acetylphenyl)piperazine-1-carbonyl)indolin-2-one
• 英文别名: 5-[4-(4-Acetylphenyl)piperazine-1-carbonyl]-1,3-dihydroindol-2-one
• CAS: 1374752-85-8
• 化学式: C₂₁H₂₁N₃O₃
• 分子量: 363.416
• InChiKey: YVJHAYUOJJPNIV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  69.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  5-羧基吲哚-2-酮 、 4-哌嗪苯乙酮 在 4-二甲氨基吡啶 、 1,2-二氯乙烷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 5-(4-(4-acetylphenyl)piperazine-1-carbonyl)indolin-2-one
  参考文献：
  名称：

  Discovery of a Novel Noniminosugar Acid α Glucosidase Chaperone Series

  摘要：

  Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid a-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.

  DOI：

  10.1021/jm3005543

文献信息

• [EN] ALPHA-GLUCOSIDASE BINDERS AND METHODS OF THEIR USE<br/>[FR] LIANTS ALPHA-GLUCOSIDASE ET LEURS PROCÉDÉS D'UTILISATION
  申请人：US SECRETARY DEPT OF HEALTH AND HUMAN SERVICES OFFICE OF TECHNOLOGY TRANSFER

  公开号：WO2012061597A1

  公开（公告）日：2012-05-10

  Compounds that bind to acid alpha glucosidase are described. Methods of using these compounds for the treatment of diabetes and Pompe disease are also described.

  描述了与酸性α葡萄糖苷酶结合的化合物。还描述了利用这些化合物治疗糖尿病和庞贝病的方法。
• Discovery of a Novel Noniminosugar Acid α Glucosidase Chaperone Series
  作者：Jingbo Xiao、Wendy Westbroek、Omid Motabar、Wendy A. Lea、Xin Hu、Arash Velayati、Wei Zheng、Noel Southall、Ann Marie Gustafson、Ehud Goldin、Ellen Sidransky、Ke Liu、Anton Simeonov、Rafael J. Tamargo、Antonia Ribes、Leslie Matalonga、Marc Ferrer、Juan J. Marugan

  DOI：10.1021/jm3005543

  日期：2012.9.13

  Pompe disease is an autosomal recessive lysosomal storage disorder (LSD) caused by deficiency of the lysosomal enzyme acid a-glucosidase (GAA). Many disease-causing mutated GAA retain enzymatic activity but are not translocated from endoplasmic reticulum (ER) to lysosomes. Enzyme replacement therapy (ERT) is the only treatment for Pompe disease but remains expensive, inconvenient, and does not reverse all disease manifestations. It was postulated that small molecules which aid in protein folding and translocation to lysosomes could provide an alternate to ERT. Previously, several iminosugars have been proposed as small-molecule chaperones for specific LSDs. Here we identified a novel series of noniminosugar chaperones for GAA. These moderate GAA inhibitors are shown to bind and thermostabilize GAA and increase GAA translocation to lysosomes in both wild-type and Pompe fibroblasts. AMDE and physical properties studies indicate that this series is a promising lead for further pharmacokinetic evaluation and testing in Pompe disease models.