2,4-bis(4-fluorobenzyloxy)benzaldehyde | 351066-29-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2,4-bis(4-fluorobenzyloxy)benzaldehyde
• 英文别名: Benzaldehyde, 2,4-di(4-fluorobenzyloxy)-；2,4-bis[(4-fluorophenyl)methoxy]benzaldehyde
• CAS: 351066-29-0
• 化学式: C₂₁H₁₆F₂O₃
• 分子量: 354.353
• InChiKey: QNUKBXVCDKLXCM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  35.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,4-bis(4-fluorobenzyloxy)benzaldehyde 、 间氨基苯甲酸 在 三乙酰氧基硼氢化钠 、 溶剂黄146 作用下， 以 甲苯 、 四氢呋喃 为溶剂， 反应 14.0h， 以59%的产率得到3-((2,4-bis((4-fluorobenzyl)oxy)benzyl)amino)benzoic acid
  参考文献：
  名称：

  Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders

  摘要：

  Peroxisome proliferator-activated receptor alpha (PPAR alpha) is expressed in retinal Muller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPAR alpha with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPAR alpha is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPAR alpha over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.

  DOI：

  10.1021/acs.jmedchem.9b01189
• 作为产物：
  描述：

  4-氟氯苄 、 2,4-二羟基苯甲醛 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.0h， 以97%的产率得到2,4-bis(4-fluorobenzyloxy)benzaldehyde
  参考文献：
  名称：

  Novel thiazolidinedione derivatives with anti-obesity effects: Dual action as PTP1B inhibitors and PPAR-γ activators

  摘要：

  Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 18l, the lowest, bore an IC50 of 1.3 mu M. In a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) promoter reporter gene assay, 18l was found to activate the transcription of the reporter gene with potencies comparable to those of troglitazone, rosiglitazone, and pioglitazone. In vivo efficacy of 18l as an anti-obesity and hypoglycemic agent was evaluated in a mouse model system. Compound 18l significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA without overt toxic effects. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.08.130

文献信息

• Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders
  作者：Xiaozheng Dou、Dinesh Nath、Henry Shin、Elmar Nurmemmedov、Philip C. Bourne、Jian-Xing Ma、Adam S. Duerfeldt

  DOI：10.1021/acs.jmedchem.9b01189

  日期：2020.3.26

  Peroxisome proliferator-activated receptor alpha (PPAR alpha) is expressed in retinal Muller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPAR alpha with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPAR alpha is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPAR alpha over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.
• Novel thiazolidinedione derivatives with anti-obesity effects: Dual action as PTP1B inhibitors and PPAR-γ activators
  作者：Bharat Raj Bhattarai、Bhooshan Kafle、Ji-Sun Hwang、Seung Wook Ham、Keun-Hyeung Lee、Hwangseo Park、Inn-Oc Han、Hyeongjin Cho

  DOI：10.1016/j.bmcl.2010.08.130

  日期：2010.11

  Benzylidene-2,4-thiazolidinedione derivatives with substitutions at both the ortho and para-positions of the phenyl group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 18l, the lowest, bore an IC50 of 1.3 mu M. In a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) promoter reporter gene assay, 18l was found to activate the transcription of the reporter gene with potencies comparable to those of troglitazone, rosiglitazone, and pioglitazone. In vivo efficacy of 18l as an anti-obesity and hypoglycemic agent was evaluated in a mouse model system. Compound 18l significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA without overt toxic effects. (C) 2010 Elsevier Ltd. All rights reserved.