3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)benzonitrile

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)benzonitrile
• 英文别名: 3-Methyl-4-[[4-(trifluoromethyl)phenyl]methoxy]benzonitrile
• 化学式: C₁₆H₁₂F₃NO
• 分子量: 291.273
• InChiKey: OFDKLUBSYQVEGJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  33
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)benzonitrile 在 盐酸 、 O‑(6‑chlorobezotriazol‑1‑yl)‑N,N,N,N‑tetramethyluronium hexafluorophosphate 、 盐酸羟胺 、 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 25.0h， 生成 (S)-2-(3-(3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-1,2,4-oxadiazol-5-yl)pyrrolidine-1-carboximidamide hydrochloride
  参考文献：
  名称：

  Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity

  摘要：

  The sphingosine-l-phosphate (SIP) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of SIP has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis. While inhibitors of both SphKs have been reported, improvements in potency and selectivity are still needed. Toward that end, we performed structure-activity relationship profiling of 8 (SLM6031434) and discovered a heretofore unrecognized side cavity that increased inhibitor potency toward SphK2. Interrogating this region revealed that relatively small hydrophobic moieties are preferred, with 10 being the most potent SphK2-selective inhibitor (K-i = 89 nM, 73-fold SphK2-selective) with validated in vivo activity.

  DOI：

  10.1021/acs.jmedchem.9b01508
• 作为产物：
  描述：

  4-(三氟甲基)苄醇 、 4-氟-3-甲基苯腈 在 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 反应 16.08h， 以54%的产率得到3-methyl-4-((4-(trifluoromethyl)benzyl)oxy)benzonitrile
  参考文献：
  名称：

  Discovery of a Small Side Cavity in Sphingosine Kinase 2 that Enhances Inhibitor Potency and Selectivity

  摘要：

  The sphingosine-l-phosphate (SIP) signaling pathway is an attractive drug target due to its involvement in immune cell chemotaxis and vascular integrity. The formation of S1P is catalyzed by sphingosine kinase 1 or 2 (SphK1 or SphK2) from sphingosine (Sph) and ATP. Inhibition of SphK1 and SphK2 to attenuate levels of SIP has been reported to be efficacious in animal models of diseases such as cancer, sickle cell disease, and renal fibrosis. While inhibitors of both SphKs have been reported, improvements in potency and selectivity are still needed. Toward that end, we performed structure-activity relationship profiling of 8 (SLM6031434) and discovered a heretofore unrecognized side cavity that increased inhibitor potency toward SphK2. Interrogating this region revealed that relatively small hydrophobic moieties are preferred, with 10 being the most potent SphK2-selective inhibitor (K-i = 89 nM, 73-fold SphK2-selective) with validated in vivo activity.

  DOI：

  10.1021/acs.jmedchem.9b01508