2-chloro-4-[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-ylmethoxy]benzoic acid | 933799-64-5

• 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: 2-chloro-4-[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-ylmethoxy]benzoic acid
• 英文别名: 2-chloro-4-{[5-isopropyl-3-(2,6-dichlorophenyl)-isoxazol-4-yl]methoxy}benzoic acid；2-Chloro-4-[[3-(2,6-dichlorophenyl)-5-propan-2-yl-1,2-oxazol-4-yl]methoxy]benzoic acid
• CAS: 933799-64-5
• 化学式: C₂₀H₁₆Cl₃NO₄
• 分子量: 440.71
• InChiKey: IFJVRFVWEKIRSN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  72.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-chloro-4-[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-ylmethoxy]benzoic acid 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 methyl 3-{2-chloro-4-[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-ylmethoxy]benzoylamino}benzoate
  参考文献：
  名称：

  Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist

  摘要：

  A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazole ring affected FXR-antagonistic activity. Compounds 15g (5-substituent: 2-naphthyl) and 15h (5-substituent: 4-biphenyl) were identified as potent antagonists with higher selectivity for FXR over progesterone receptor than the naturally occurring FXR antagonist GS. The 5-substituent is also a critical determinant of the characteristic corepressor recruitment profile of this class of FXR antagonists, though distinct mechanisms appear to be involved: 15h stabilizes the corepressor-nuclear receptor interaction, while 15g inhibits coactivator recruitment. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.01.046
• 作为产物：
  描述：

  2-氯-4-羟基苯甲酸甲酯 在 偶氮二甲酸二异丙酯 、 三苯基膦 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 生成 2-chloro-4-[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-ylmethoxy]benzoic acid
  参考文献：
  名称：

  目标跳跃是鉴定新型EphA2蛋白-蛋白拮抗剂的有用工具

  摘要：

  近年来，人们已经描述了胆酸（LCA），它是核受体FXR和G蛋白偶联受体TGR5的生理配体，它是EphA2受体的拮抗剂，EphA2受体是参与肿瘤生长的ephrin信号系统的关键成员。考虑到LCA能够识别FXR，TGR5和EphA2受体的能力，我们假设小分子结合每种受体的结构要求可能相似。因此，我们选择了一组市售的FXR或TGR5配体，并测试了它们通过靶向EphA2-ephrin-A1接口抑制EphA2的能力。在选定的化合物中，二苯乙烯羧酸GW4064被确定为EphA2的有效拮抗剂，能够在微摩尔范围内阻断前列腺癌细胞中的EphA2活化。

  DOI：

  10.1002/cmdc.201300305

文献信息

• Discovery and structural development of small molecules that enhance transport activity of bile salt export pump mutant associated with progressive familial intrahepatic cholestasis type 2
  作者：Takashi Misawa、Hisamitsu Hayashi、Yuichi Sugiyama、Yuichi Hashimoto

  DOI：10.1016/j.bmc.2012.03.016

  日期：2012.5

  Progressive familial intrahepatic cholestasis type 2 (PFIC2) is caused by hereditary mutations of bile salt export pump (BSEP), such as E297G BSEP, which is a folding-defective mutant that is unable to traffic beyond the endoplasmic reticulum (ER). 4-Phenylbutyric acid (4-PBA) enhances the cell surface expression and transport capacity of E297G BSEP, but has a relatively high dose (1 mM or more) is

  进行性2型家族性肝内胆汁淤积症（PFIC2）是由胆盐输出泵（BSEP）的遗传突变引起的，例如E297G BSEP，这是一种折叠缺陷型突变体，无法运输到内质网（ER）之外。4-苯基丁酸（4-PBA）可以增强E297G BSEP的细胞表面表达和运输能力，但需要相对较高的剂量（1 mM或更高）才能显示效果。在这里，我们表明胆汁酸可能充当药理伴侣，促进E297G BSEP的正确折叠和运输。我们还描述了对E297G BSEP具有强大药理伴侣活性的非甾体化合物的发现和结构开发。
• Target Hopping as a Useful Tool for the Identification of Novel EphA2 Protein-Protein Antagonists
  作者：Massimiliano Tognolini、Matteo Incerti、Daniele Pala、Simonetta Russo、Riccardo Castelli、Iftiin Hassan-Mohamed、Carmine Giorgio、Alessio Lodola

  DOI：10.1002/cmdc.201300305

  日期：2014.1

  ability to inhibit EphA2 by targeting the EphA2‐ephrin‐A1 interface. Among the selected compounds, the stilbene carboxylic acid GW4064 was identified as an effective antagonist of EphA2, being able to block EphA2 activation in prostate carcinoma cells, in the micromolar range. This finding proposes the “target hopping” approach as a new effective strategy to discover new protein–protein interaction inhibitors

  近年来，人们已经描述了胆酸（LCA），它是核受体FXR和G蛋白偶联受体TGR5的生理配体，它是EphA2受体的拮抗剂，EphA2受体是参与肿瘤生长的ephrin信号系统的关键成员。考虑到LCA能够识别FXR，TGR5和EphA2受体的能力，我们假设小分子结合每种受体的结构要求可能相似。因此，我们选择了一组市售的FXR或TGR5配体，并测试了它们通过靶向EphA2-ephrin-A1接口抑制EphA2的能力。在选定的化合物中，二苯乙烯羧酸GW4064被确定为EphA2的有效拮抗剂，能够在微摩尔范围内阻断前列腺癌细胞中的EphA2活化。
• Design, synthesis, and evaluation of non-steroidal farnesoid X receptor (FXR) antagonist
  作者：Masahiko Kainuma、Makoto Makishima、Yuichi Hashimoto、Hiroyuki Miyachi

  DOI：10.1016/j.bmc.2007.01.046

  日期：2007.4

  A series of substituted-isoxazole derivatives was prepared as candidate farnesoid X receptor (FXR) antagonists, based on our previously proposed ligand superfamily concept. Structure-activity relationship studies indicated that the shape and the structural bulkiness of the substituent at the 5-position of the isoxazole ring affected FXR-antagonistic activity. Compounds 15g (5-substituent: 2-naphthyl) and 15h (5-substituent: 4-biphenyl) were identified as potent antagonists with higher selectivity for FXR over progesterone receptor than the naturally occurring FXR antagonist GS. The 5-substituent is also a critical determinant of the characteristic corepressor recruitment profile of this class of FXR antagonists, though distinct mechanisms appear to be involved: 15h stabilizes the corepressor-nuclear receptor interaction, while 15g inhibits coactivator recruitment. (c) 2007 Elsevier Ltd. All rights reserved.
• Synthesis of Novel Farnesoid X Receptor Agonists and Validation of Their Efficacy in Activating Differentiation of Mouse Bone Marrow-Derived Mesenchymal Stem Cells into Osteoblasts
  作者：Ko Fujimori、Yusuke Iguchi、Yukiko Yamashita、Keigo Gohda、Naoki Teno

  DOI：10.3390/molecules24224155

  日期：——

  The modulators of farnesoid X receptor (FXR), a bile acid receptor, regulate various biological processes including bile acid metabolism, and are associated with the control of fatty liver and osteoporosis. Thus, the control of FXR activity and development of FXR modulators are critical not only for research, but also for clinical application. In this study, we synthesized novel FXR agonists 1–4 possessing isoxazole and N-substituted benzimidazole moieties, and compared their effects on osteoblast differentiation with the known FXR agonists, chenodeoxycholic acid and a synthetic compound, GW4064. Two (3 and 4) of the four novel FXR agonists 1–4 showed high specificities for FXR. Computer-assisted modeling suggested that the binding of the FXR agonist 3 with ligand binding domain of FXR was similar to GW4064. FXR was expressed in mouse bone marrow-derived mesenchymal stem cell (MSC)-like ST2 cells (ST-2 MSCs). The FXR agonists activated the BMP-2-induced differentiation of ST-2 MSCs into osteoblasts and enhanced the expression of RUNX2. Moreover, the potency of the FXR agonist 3 was comparable to GW4064 in promoting osteoblast differentiation of ST-2 MSCs. These results indicate that FXR activation enhanced the BMP-2-induced differentiation of MSCs into osteoblasts through activating RUNX2 expression. FXR could be a potential therapeutic target for the treatment of bone diseases such as osteoporosis.

  法尼索尔X受体（FXR）的调节剂，一种胆酸受体，调节包括胆酸代谢在内的各种生物过程，并与控制脂肪肝和骨质疏松有关。因此，不仅对于研究，而且对于临床应用来说，控制FXR活性和开发FXR调节剂至关重要。在这项研究中，我们合成了具有异噁唑和N-取代苯并咪唑基团的新型FXR激动剂1-4，并将它们与已知的FXR激动剂，烯二氧胆酸和合成化合物GW4064的效果进行了比较。四种新型FXR激动剂1-4中的两种（3和4）显示出对FXR的高特异性。计算机辅助建模表明，FXR激动剂3与FXR的配体结合结构域的结合类似于GW4064。FXR在小鼠骨髓来源的间充质干细胞（MSC）样ST2细胞（ST-2 MSCs）中表达。FXR激动剂激活了BMP-2诱导的ST-2 MSCs向成骨细胞的分化，并增强了RUNX2的表达。此外，FXR激动剂3在促进ST-2 MSCs成骨细胞分化方面的效力与GW4064相当。这些结果表明，FXR激活通过激活RUNX2表达增强了BMP-2诱导的MSCs向成骨细胞的分化。FXR可能是治疗骨质疏松等骨疾病的潜在治疗靶点。