CMB-086882-1 | 1227692-57-0

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: CMB-086882-1
• CAS: 1227692-57-0
• 化学式: C₁₀H₉ClN₂OS
• 分子量: 242.7
• InChiKey: KNBMOSHSMIPGFM-ULRYTFMMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.65
• 重原子数：
  15.0
• 可旋转键数：
  3.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  48.65
• 氢给体数：
  2.0
• 氢受体数：
  2.0

反应信息

• 作为产物：
  描述：

  4-[(4-氯苯基)硫代]-3-氧代丁酸乙酯 在 碳酸氢钠 、 [¹⁵N₂]-hydrazinium sulfate 作用下， 以 乙醇 、 水 为溶剂， 以0.21 g的产率得到CMB-086882-1
  参考文献：
  名称：

  ADME-Guided Design and Synthesis of Aryloxanyl Pyrazolone Derivatives To Block Mutant Superoxide Dismutase 1 (SOD1) Cytotoxicity and Protein Aggregation: Potential Application for the Treatment of Amyotrophic Lateral Sclerosis

  摘要：

  Amyotrophic lateral sclerosis (ALS) is an orphan neurodegenerative disease currently without a cure: The arylsulfanyl pyrazolone (ASP) scaffold was one of the active scaffolds identified in a cell-based high throughput screening assay targeting mutant Cu/Zn superoxide dismutase 1 (SOD 1) induced toxicity and aggregation as a marker for ALS. The initial ASP hit compounds were potent and had favorable ADME properties but had poor microsomal and plasma stability. Here, we identify the microsomal metabolite and describe synthesized analogues of these ASP compounds to address the rapid metabolism. Both in vitro potency and pharmacological properties of the ASP scaffold have been dramatically improved via chemical modification to the corresponding sulfone and ether derivatives. One of the ether analogues (13), with superior potency and in vitro pharmacokinetic properties, was tested in vivo for its pharmacokinetic profile, brain penetration, and efficacy in an ALS mouse model. The analogue showed sustained blood and brain levels in vivo and significant activity in the mouse model of ALS, thus validating the new aryloxanyl pyrazolone scaffold as an important novel therapeutic lead for the treatment of this neurodegenerative disorder.

  DOI：

  10.1021/jm2014277