2-(4,6-bis(4-(trifluoromethoxy)phenethoxy)pyrimidin-2-ylthio)hexanoic acid | 1231733-75-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 2-(4,6-bis(4-(trifluoromethoxy)phenethoxy)pyrimidin-2-ylthio)hexanoic acid
• 英文别名: 2-[4,6-bis[2-[4-(trifluoromethoxy)phenyl]ethoxy]pyrimidin-2-yl]sulfanylhexanoic acid
• CAS: 1231733-75-7
• 化学式: C₂₈H₂₈F₆N₂O₆S
• 分子量: 634.597
• InChiKey: PDDCQAHTKIBSGG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  9.4
• 重原子数：
  43
• 可旋转键数：
  16
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  125
• 氢给体数：
  1
• 氢受体数：
  15

反应信息

• 作为产物：
  描述：

  ethyl 2-(4,6-bis(4-(trifluoromethoxy)phenethoxy)pyrimidin-2-ylthio)hexanoate 在 水 、 lithium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.0h， 以97%的产率得到2-(4,6-bis(4-(trifluoromethoxy)phenethoxy)pyrimidin-2-ylthio)hexanoic acid
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity

  摘要：

  We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPAR gamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(A beta 42) = 22.8 mu M, EC50(PPAR gamma) = 8.3 mu M). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (A beta 42)-lowering NSAIDs for gamma-secretase and glitazones for PPAR gamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPAR gamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPAR gamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC50(A beta 42) = 6.0 mu M, EC50(PPAR gamma) = 11.0 mu M) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(A beta 42) = 5.1 mu M, EC50(PPAR gamma) = 6.6 mu M).

  DOI：

  10.1021/jm1003073

文献信息

• Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity
  作者：Martina Hieke、Julia Ness、Ramona Steri、Michaela Dittrich、Christine Greiner、Oliver Werz、Karlheinz Baumann、Manfred Schubert-Zsilavecz、Sascha Weggen、Heiko Zettl

  DOI：10.1021/jm1003073

  日期：2010.6.24

  We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPAR gamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(A beta 42) = 22.8 mu M, EC50(PPAR gamma) = 8.3 mu M). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (A beta 42)-lowering NSAIDs for gamma-secretase and glitazones for PPAR gamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPAR gamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPAR gamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC50(A beta 42) = 6.0 mu M, EC50(PPAR gamma) = 11.0 mu M) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(A beta 42) = 5.1 mu M, EC50(PPAR gamma) = 6.6 mu M).