[4-(1-naphthylmethoxy)phenyl]acetic acid | 125721-57-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: [4-(1-naphthylmethoxy)phenyl]acetic acid
• 英文别名: 2-[4-(Naphthalen-1-ylmethoxy)phenyl]acetic acid
• CAS: 125721-57-5
• 化学式: C₁₉H₁₆O₃
• 分子量: 292.334
• InChiKey: GJKQTSSKZKSWDV-UHFFFAOYSA-N

物化性质

• 沸点：
  507.0±30.0 °C(Predicted)
• 密度：
  1.240±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [4-(1-naphthylmethoxy)phenyl]acetic acid 在 盐酸 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 2.25h， 生成 (S)-2-amino-3-(2-(4-(naphthalen-1-ylmethoxy)phenyl)acetamido)propanoic acid hydrochloride
  参考文献：
  名称：

  WO2023/19244

  摘要：

  公开号：
• 作为产物：
  描述：

  methyl 2-(4-(naphthalen-1-ylmethoxy)phenyl)acetate 在 水 、 potassium hydroxide 作用下， 以 甲醇 为溶剂， 生成 [4-(1-naphthylmethoxy)phenyl]acetic acid
  参考文献：
  名称：

  WO2023/19244

  摘要：

  公开号：

文献信息

• Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect
  作者：Elix Alberto Domínguez-Mendoza、Yelzyn Galván-Ciprés、Josué Martínez-Miranda、Cristian Miranda-González、Blanca Colín-Lozano、Emanuel Hernández-Núñez、Gloria I. Hernández-Bolio、Oscar Palomino-Hernández、Gabriel Navarrete-Vazquez

  DOI：10.3390/molecules26040799

  日期：——

  Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation.

  设计了苯乙酸取代物（1-3）、苯丙酸取代物（4-6）和苄基噻唑烷二酮（7-9）衍生物，根据已显示出强大抗糖尿病活性的多靶点统一药效团模式。这种生物活性是由于同时对PPARα、PPARγ和GPR40受体的多药效学刺激以及对醛糖还原酶（AR）和蛋白酪氨酸磷酸酶1B（PTP-1B）的酶抑制作用。这九种化合物共享相同的四个药效团元素：酸基团、芳香环、庞大疏水基团和两个元素之间的灵活连接剂。进行了加成和取代反应以获得中等产率的分子。进行了体外药理共识分析（PHACA），以确定它们可能的作用方式、蛋白亲和性、毒理活性和药物样性质。将结果与体内实验结合，评估这些化合物在100 mg/kg单剂量下降低糖尿病小鼠血糖水平的能力。化合物6（苯丙酸衍生物）和9（苄基噻唑烷二酮衍生物）在2型糖尿病小鼠模型中以显著方式改善高血糖峰值。最后，对表现最佳的化合物进行了分子动力学模拟，以揭示它们的作用机制。模拟显示了AR结合口袋的灵活性，并显示在模拟时间内两种化合物都保持结合，尽管结合方式不同。总之，我们设计了九种具有强大体内抗高血糖活性的酸类生物同位素，预测具有良好的药代动力学和毒理学特性。这些发现共同证明了我们采用的分子设计，其中统一的药效团由于其多靶点激活而具有强大的抗糖尿病作用。
• WO2023/19244
  申请人：——

  公开号：——

  公开（公告）日：——