N-(2,3-dihydro-1H-inden-2-yl)-5-isopropylisoxazole-3-carboxamide

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: N-(2,3-dihydro-1H-inden-2-yl)-5-isopropylisoxazole-3-carboxamide
• 英文别名: N-(2,3-dihydro-1H-inden-2-yl)-5-propan-2-yl-1,2-oxazole-3-carboxamide
• 化学式: C₁₆H₁₈N₂O₂
• 分子量: 270.331
• InChiKey: HXDRVYPNEBSTOK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  5-异丙基异恶唑-3-羧酸 、 2-氨基茚 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 生成 N-(2,3-dihydro-1H-inden-2-yl)-5-isopropylisoxazole-3-carboxamide
  参考文献：
  名称：

  Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy

  摘要：

  Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.

  DOI：

  10.1021/acs.jmedchem.6b01885

文献信息

• Discovery of a Small Molecule Probe That Post-Translationally Stabilizes the Survival Motor Neuron Protein for the Treatment of Spinal Muscular Atrophy
  作者：Anne Rietz、Hongxia Li、Kevin M. Quist、Jonathan J. Cherry、Christian L. Lorson、Barrington G. Burnett、Nicholas L. Kern、Alyssa N. Calder、Melanie Fritsche、Hrvoje Lusic、Patrick J. Boaler、Sungwoon Choi、Xuechao Xing、Marcie A. Glicksman、Gregory D. Cuny、Elliot J. Androphy、Kevin J. Hodgetts

  DOI：10.1021/acs.jmedchem.6b01885

  日期：2017.6.8

  Spinal muscular atrophy (SMA) is the leading genetic cause of infant death. We previously developed a high throughput assay that employs an SMN2-luciferase reporter allowing identification of compounds that act transcriptionally, enhance exon recognition, or stabilize the SMN protein. We describe optimization and characterization of an analog suitable for in vivo testing. Initially, we identified analog 4m that had good in vitro properties but low plasma and brain exposure in a mouse PK experiment due to short plasma stability; this was overcome by reversing the amide bond and changing the heterocycle. Thiazole 27 showed excellent in vitro properties and a promising mouse PK profile, making it suitable for in vivo testing. This series post-translationally stabilizes the SMN protein, unrelated to global proteasome or autophagy inhibition, revealing a novel therapeutic mechanism that should complement other modalities for treatment of SMA.