methyl 4-((4-formyl-2-methoxyphenoxy)methyl)benzoate | 351336-10-2

• 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: methyl 4-((4-formyl-2-methoxyphenoxy)methyl)benzoate
• 英文别名: Methyl 4-[(4-formyl-2-methoxyphenoxy)methyl]benzoate
• CAS: 351336-10-2
• 化学式: C₁₇H₁₆O₅
• mdl: MFCD01893327
• 分子量: 300.311
• InChiKey: SXQFUFPFCNTWEB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  22
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.176
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl 4-((4-formyl-2-methoxyphenoxy)methyl)benzoate 在 水 、 sodium hydroxide 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 生成 4-[(4-formyl-2-methoxyphenoxy)methyl]benzoic acid
  参考文献：
  名称：

  Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin

  摘要：

  Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX LPA signaling axis has been implicated in diverse physiological and pathological processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore targeting ATX with small molecule inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compounds inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC50 = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.

  DOI：

  10.1021/jm1005012
• 作为产物：
  描述：

  4-溴甲基苯甲酸甲酯 、 香草醛 在 potassium hydroxide 作用下， 生成 methyl 4-((4-formyl-2-methoxyphenoxy)methyl)benzoate
  参考文献：
  名称：

  Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation

  摘要：

  Autotaxin（ATX）是一种分泌的核苷酸焦磷酸酶/磷酸二酯酶，作为一种溶酶磷脂酶D，产生脂质介质溶酶磷脂酸（LPA），是许多细胞类型的有丝分裂原、趋化因子和生存因子。ATX-LPA信号通路已被认为在血管生成、慢性炎症、纤维化疾病和肿瘤进展中起作用，使得这个系统成为治疗的有吸引力的目标。然而，目前没有有效和选择性的非脂类ATX抑制剂。通过筛选化学库，我们已经确定了噻唑烷二酮，这些噻唑烷二酮能够选择性地抑制体外和体内ATX介导的LPA产生。抑制剂的效力在加入硼酸基团后大约提高了100倍（IC50约为30 nM），设计该基团是为了靶向ATX中的活性位点苏氨酸（T210）。将该抑制剂静脉注射到小鼠体内，导致血浆LPA水平出现惊人的快速下降，表明循环中LPA的周转比以前估计的要动态得多。因此，基于硼酸的小分子化合物有望成为用于靶向ATX的候选药物。

  DOI：

  10.1073/pnas.1001529107

文献信息

• Boronic acid-based inhibitor of autotaxin reveals rapid turnover of LPA in the circulation
  作者：Harald M. H. G. Albers、Anping Dong、Laurens A. van Meeteren、David A. Egan、Manjula Sunkara、Erica W. van Tilburg、Karianne Schuurman、Olaf van Tellingen、Andrew J. Morris、Susan S. Smyth、Wouter H. Moolenaar、Huib Ovaa

  DOI：10.1073/pnas.1001529107

  日期：2010.4.20

  Autotaxin (ATX) is a secreted nucleotide pyrophosphatase/phosphodiesterase that functions as a lysophospholipase D to produce the lipid mediator lysophosphatidic acid (LPA), a mitogen, chemoattractant, and survival factor for many cell types. The ATX-LPA signaling axis has been implicated in angiogenesis, chronic inflammation, fibrotic diseases and tumor progression, making this system an attractive target for therapy. However, potent and selective nonlipid inhibitors of ATX are currently not available. By screening a chemical library, we have identified thiazolidinediones that selectively inhibit ATX-mediated LPA production both in vitro and in vivo. Inhibitor potency was approximately 100-fold increased (IC ₅₀  ∼ 30 nM) after the incorporation of a boronic acid moiety, designed to target the active-site threonine (T210) in ATX. Intravenous injection of this inhibitor into mice resulted in a surprisingly rapid decrease in plasma LPA levels, indicating that turnover of LPA in the circulation is much more dynamic than previously appreciated. Thus, boronic acid-based small molecules hold promise as candidate drugs to target ATX.

  Autotaxin（ATX）是一种分泌的核苷酸焦磷酸酶/磷酸二酯酶，作为一种溶酶磷脂酶D，产生脂质介质溶酶磷脂酸（LPA），是许多细胞类型的有丝分裂原、趋化因子和生存因子。ATX-LPA信号通路已被认为在血管生成、慢性炎症、纤维化疾病和肿瘤进展中起作用，使得这个系统成为治疗的有吸引力的目标。然而，目前没有有效和选择性的非脂类ATX抑制剂。通过筛选化学库，我们已经确定了噻唑烷二酮，这些噻唑烷二酮能够选择性地抑制体外和体内ATX介导的LPA产生。抑制剂的效力在加入硼酸基团后大约提高了100倍（IC50约为30 nM），设计该基团是为了靶向ATX中的活性位点苏氨酸（T210）。将该抑制剂静脉注射到小鼠体内，导致血浆LPA水平出现惊人的快速下降，表明循环中LPA的周转比以前估计的要动态得多。因此，基于硼酸的小分子化合物有望成为用于靶向ATX的候选药物。
• WO2023/84158
  申请人：——

  公开号：——

  公开（公告）日：——
• Discovery and Optimization of Boronic Acid Based Inhibitors of Autotaxin
  作者：Harald M. H. G. Albers、Laurens A. van Meeteren、David A. Egan、Erica W. van Tilburg、Wouter H. Moolenaar、Huib Ovaa

  DOI：10.1021/jm1005012

  日期：2010.7.8

  Autotaxin (ATX) is an extracellular enzyme that hydrolyzes lysophosphatidylcholine (LPC) to produce the lipid mediator lysophosphatidic acid (LPA). The ATX LPA signaling axis has been implicated in diverse physiological and pathological processes, including vascular development, inflammation, fibrotic disease, and tumor progression. Therefore targeting ATX with small molecule inhibitors is an attractive therapeutic strategy. We recently reported that 2,4-thiazolidinediones inhibit ATX activity in the micromolar range. Interestingly, inhibitory potency was dramatically increased by introduction of a boronic acid moiety, designed to target the active site threonine in ATX. Here we report on the discovery and further optimization of boronic acid based ATX inhibitors. The most potent of these compounds inhibits ATX-mediated LPC hydrolysis in the nanomolar range (IC50 = 6 nM). The finding that ATX can be targeted by boronic acids may aid the development of ATX inhibitors for therapeutic use.
• SP1-independent inhibition of FOXM1 by modified thiazolidinediones
  作者：Seyed Amirhossein Tabatabaei Dakhili、David J. Pérez、Keshav Gopal、Moinul Haque、John R. Ussher、Khosrow Kashfi、Carlos A. Velázquez-Martínez

  DOI：10.1016/j.ejmech.2020.112902

  日期：2021.1