2-fluoro-5-{2-[(4S)-4-(4-methyl-1,1-dioxo-1λ⁶-thian-4-yl)-2-oxopyrrolidin-1-yl]ethoxy}benzonitrile

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-fluoro-5-{2-[(4S)-4-(4-methyl-1,1-dioxo-1λ⁶-thian-4-yl)-2-oxopyrrolidin-1-yl]ethoxy}benzonitrile
• 英文别名: Lp-PLA2-IN-2；2-fluoro-5-[2-[(4S)-4-(4-methyl-1,1-dioxothian-4-yl)-2-oxopyrrolidin-1-yl]ethoxy]benzonitrile
• 化学式: C₁₉H₂₃FN₂O₄S
• 分子量: 394.467
• InChiKey: SYEMWCXBADSSGE-OAHLLOKOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  95.8
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氟-5-羟基苯甲腈 在 sodium hydride 、 potassium carbonate 、 三乙胺 、 间氯过氧苯甲酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 40.5h， 生成 2-fluoro-5-{2-[(4R)-4-(4-methyl-1,1-dioxo-1λ⁶-thian-4-yl)-2-oxopyrrolidin-1-yl]ethoxy}benzonitrile 、 2-fluoro-5-{2-[(4S)-4-(4-methyl-1,1-dioxo-1λ⁶-thian-4-yl)-2-oxopyrrolidin-1-yl]ethoxy}benzonitrile
  参考文献：
  名称：

  Fragment-Based Approach to the Development of an Orally Bioavailable Lactam Inhibitor of Lipoprotein-Associated Phospholipase A2 (Lp-PLA₂)

  摘要：

  Lp-PLA(2) has been explored as a target for a number of inflammation associated diseases, including cardiovascular disease and dementia. This article describes the discovery of a new fragment derived chemotype that interacts with the active site of Lp-PLA(2). The starting fragment hit was discovered through an X-ray fragment screen and showed no activity in the bioassay (IC50 > 1 mM). The fragment hit was optimized using a variety of structure-based drug design techniques, including virtual screening, fragment merging, and improvement of shape complementarity. A novel series of Lp-PLA(2) inhibitors was generated with low lipophilicity and a promising pharmacokinetic profile.

  DOI：

  10.1021/acs.jmedchem.6b01427