3-(3,5-dimethylisoxazol-4-yl)-5-hydroxybenzaldehyde | 1429129-61-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-(3,5-dimethylisoxazol-4-yl)-5-hydroxybenzaldehyde
• 英文别名: 3-(3,5-Dimethyl-1,2-oxazol-4-yl)-5-hydroxybenzaldehyde；3-(3,5-dimethyl-1,2-oxazol-4-yl)-5-hydroxybenzaldehyde
• CAS: 1429129-61-2
• 化学式: C₁₂H₁₁NO₃
• 分子量: 217.224
• InChiKey: SAXQPZMUAKVIHP-UHFFFAOYSA-N

物化性质

• 沸点：
  395.5±42.0 °C(Predicted)
• 密度：
  1.252±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  63.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(3,5-dimethylisoxazol-4-yl)-5-hydroxybenzaldehyde 在 manganese(IV) oxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 54.0h， 生成 (3-(3,5-dimethylisoxazol-4-yl)-5-hydroxyphenyl)(phenyl)methanone
  参考文献：
  名称：

  Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands

  摘要：

  The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives to develop potent inhibitors of the BET (bromodomain and extra terminal domain) bromodomain family with good ligand efficiency. X-ray crystal structures of the most potent compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that the phenol and acetate derivatives of the lead compounds showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, as shown for other BET bromodomain inhibitors and genetic BRD4 knockdown, whereas the reported compounds showed no general cytotoxicity in other cancer cell lines tested.

  DOI：

  10.1021/jm301588r
• 作为产物：
  描述：

  3-溴-5-硝基苯甲醛 在 四(三苯基膦)钯 、 硫酸 、 铁粉 、 sodium carbonate 、 氯化铵 、 对甲苯磺酸 、 溶剂黄146 、 sodium nitrite 作用下， 以 乙醇 、 水 、 甲苯 为溶剂， 反应 36.0h， 生成 3-(3,5-dimethylisoxazol-4-yl)-5-hydroxybenzaldehyde
  参考文献：
  名称：

  Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3,5-dimethylisoxazole

  摘要：

  GPR40 is an attractive target due to its glucose-stimulated insulin secretion effect with low risk of causing hypoglycemia, which also can be seen from the clinical studies using TAK-875 (fasiglifam). In the present studies, we discovered a series of analogues containing 3,5-dimethylisoxazole as potent GPR40 agonists, especially compound ilk with an EC50 value of 15.9 nM. Moreover, compound 11k reduced glucose excursion to 23.1% in ICR mice and 29.5% in type 2 diabetic C57BL/6 mice at 30 mg/kg. It also exhibited satisfactory PK profile. Docking studies were conducted to explain the interaction mode of this series. In summary, compound 11k with robust efficacy in vitro and in vivo is a promising drug candidate for further investigation. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.03.054

文献信息

• COMPOUND WITH ANTICANCER ACTIVITY
  申请人：KYOWA KIRIN CO., LTD.

  公开号：US20210024540A1

  公开（公告）日：2021-01-28

  A compound having anticancer activity, or a pharmaceutically acceptable salt thereof is provided. Used is a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof: (wherein, L 1 and L 2 are the same or different and each represents a group represented by one formula selected from the group consisting of formulas (A) to (F), and S represents a group represented by one formula selected from the group consisting of formulas (S1) to (S18)).

  提供具有抗癌活性的化合物，或其药用可接受的盐。所使用的化合物表示为以下式（I）或其药用可接受的盐： （其中，L1和L2相同或不同，每个代表从(A)到(F)式组成的一种式子所代表的基团，S代表从(S1)到(S18)式组成的一种式子所代表的基团）。
• BET DEGRADER
  申请人：Kyowa Kirin Co., Ltd.

  公开号：EP4039333A1

  公开（公告）日：2022-08-10

  The present invention provides a BET (protein) degrader, specifically a BET degrader containing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof: wherein L1 and L2 are the same or different and each represents a small molecular ligand for BET protein, and S represents a group represented by a formula selected from the group consisting of formulas (SI) to (S18).

  本发明提供了一种BET（蛋白质）降解剂，具体地说，是一种含有由公式（I）或其药学上可接受的盐所表示的化合物的BET降解剂： 其中L1和L2相同或不同，每个代表BET蛋白质的小分子配体，S代表从公式组成的选择公式所表示的组的群，该组包括（SI）到（S18）的公式。
• BET bromodomain ligands: Probing the WPF shelf to improve BRD4 bromodomain affinity and metabolic stability
  作者：Laura E. Jennings、Matthias Schiedel、David S. Hewings、Sarah Picaud、Corentine M.C. Laurin、Paul A. Bruno、Joseph P. Bluck、Amy R. Scorah、Larissa See、Jessica K. Reynolds、Mustafa Moroglu、Ishna N. Mistry、Amy Hicks、Pavel Guzanov、James Clayton、Charles N.G. Evans、Giulia Stazi、Philip C. Biggin、Anna K. Mapp、Ester M. Hammond、Philip G. Humphreys、Panagis Filippakopoulos、Stuart J. Conway

  DOI：10.1016/j.bmc.2018.05.003

  日期：2018.7

  Ligands for the bromodomain and extra terminal domain (BET) family of bromodomains have shown promise as useful therapeutic agents for treating a range of cancers and inflammation. Here we report that our previously developed 3,5-dimethylisoxazole-based BET bromodomain ligand (OXFBD02) inhibits interactions of BRD4(1) with the ReIA subunit of NF-kappa B, in addition to histone H4. This ligand shows a promising profile in a screen of the NCI-60 panel but was rapidly metabolised (t(1/2) = 39.8 min). Structure-guided optimisation of compound properties led to the development of the 3-pyridyl-derived OXFBD04. Molecular dynamics simulations assisted our understanding of the role played by an internal hydrogen bond in altering the affinity of this series of molecules for BRD4(1). OXFBDO4 shows improved BRD4(1) affinity (IC50 = 166 nM), optimised physicochemical properties (LE = 0.43; LLE = 5.74; SFI = 5.96), and greater metabolic stability (t(1/2) = 388 min). (C) 2018 The Authors. Published by Elsevier Ltd.
• [EN] BET DEGRADER<br/>[FR] AGENT DE DÉGRADATION DE BET<br/>[JA] ＢＥＴ分解剤
  申请人：KYOWA KIRIN CO LTD

  公开号：WO2021065980A1

  公开（公告）日：2021-04-08

  BET分解剤を提供する。下記式(I)で表される化合物またはその薬学的に許容される塩を含むBET分解剤を用いる： (式中、L1およびL2は、それぞれ同一または異なって、BETタンパク質に対する低分子リガンドを表し、Sは、式(S1)～(S18)からなる群から選択される1つの式で表される基を表す)。
• Synthesis and biological evaluation of GPR40/FFAR1 agonists containing 3,5-dimethylisoxazole
  作者：Lingyun Yang、Jian Zhang、Lianghui Si、Li Han、Bo Zhang、Hui Ma、Junhao Xing、Leilei Zhao、Jinpei Zhou、Huibin Zhang

  DOI：10.1016/j.ejmech.2016.03.054

  日期：2016.6

  GPR40 is an attractive target due to its glucose-stimulated insulin secretion effect with low risk of causing hypoglycemia, which also can be seen from the clinical studies using TAK-875 (fasiglifam). In the present studies, we discovered a series of analogues containing 3,5-dimethylisoxazole as potent GPR40 agonists, especially compound ilk with an EC50 value of 15.9 nM. Moreover, compound 11k reduced glucose excursion to 23.1% in ICR mice and 29.5% in type 2 diabetic C57BL/6 mice at 30 mg/kg. It also exhibited satisfactory PK profile. Docking studies were conducted to explain the interaction mode of this series. In summary, compound 11k with robust efficacy in vitro and in vivo is a promising drug candidate for further investigation. (C) 2016 Elsevier Masson SAS. All rights reserved.