methyl 3-chloro-4,6-dihydroxy-2-(2-(1-phenyl-1H-imidazol-2-yl)ethyl)benzoate | 1380296-81-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: methyl 3-chloro-4,6-dihydroxy-2-(2-(1-phenyl-1H-imidazol-2-yl)ethyl)benzoate
• 英文别名: Methyl 3-chloro-4,6-dihydroxy-2-[2-(1-phenylimidazol-2-yl)ethyl]benzoate
• CAS: 1380296-81-0
• 化学式: C₁₉H₁₇ClN₂O₄
• 分子量: 372.808
• InChiKey: GUUJEYGOEWLASQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  84.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  在 四丁基氟化铵 作用下， 以 甲醇 、 水 为溶剂， 反应 0.5h， 生成 methyl 3-chloro-4,6-dihydroxy-2-(2-(1-phenyl-1H-imidazol-2-yl)ethyl)benzoate
  参考文献：
  名称：

  Development of a Grp94 inhibitor

  摘要：

  Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90 alpha/beta (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90 alpha/beta client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.

  DOI：

  10.1021/ja303477g

文献信息

• [EN] GRP94 INHIBITORS<br/>[FR] INHIBITEURS DE GRP94
  申请人：UNIV KANSAS

  公开号：WO2012139010A1

  公开（公告）日：2012-10-11

  The present disclosure provides a series of compounds which exhibit isoform selective inhibition of GRP94, a homologue of Hsp90 that is localized to the endoplasmic recticulum. Through GRP94 inhibition, these compounds are likely to manifest anti-cancer, anti-inflammatory, anti-metastasis, and immunosuppressive activities, as well as utility in the treatment of neurodegenerative diseases, and diabetes.

  本公开提供了一系列化合物，这些化合物表现出对GRP94的异构选择性抑制作用，GRP94是定位于内质网的Hsp90同源物。通过抑制GRP94，这些化合物有可能表现出抗癌、抗炎、抗转移、免疫抑制和在治疗神经退行性疾病和糖尿病方面的用途。
• Compositions and methods of treatment for myocilin glaucoma by selectively inhibiting GRP94
  申请人：Dickey Chad Anthony

  公开号：US09045434B1

  公开（公告）日：2015-06-02

  A compound and method for treating myocilin glaucoma using a selective Grp94 inhibitor is presented. Clearance of mutant myocilin can be promoted by selectively targeting the endoplasmic reticulum (ER) chaperone Grp94 using siRNA knockdown or small molecule inhibitors. Grp94 contributes to the intracellular accumulation of mutant myocilin. Tailored treatments aimed at disrupting the Grp94/mutant myocilin interaction can be used as a new therapeutic strategy for myocilin glaucoma. The inventors developed a compound having a general backbone structure of geldanamycin (GDA) and radicicol (RDC) in which a more hydrophobic surrogate of the quinone in GDA is linked to the resorcinol in RDC through a cis-amide bioisostere.

  本文提出了一种使用选择性Grp94抑制剂治疗myocilin青光眼的化合物和方法。通过选择性靶向内质网（ER）分子伴侣Grp94，使用siRNA敲除或小分子抑制剂可以促进突变myocilin的清除。 Grp94有助于突变myocilin的细胞内积累。旨在破坏Grp94 /突变myocilin相互作用的定制治疗可用作myocilin青光眼的新治疗策略。发明人开发了一种具有gelDAnamycin（GDA）和radicicol（RDC）的通用骨架结构的化合物，其中GDA中的更亲水的代用喹啉通过顺式酰胺生物同构体连接到RDC中的邻苯二酚上。
• GRP94 INHIBITORS
  申请人：Blagg Brian S.J.

  公开号：US20130109684A1

  公开（公告）日：2013-05-02

  The present disclosure provides a series of compounds which exhibit isoform selective inhibition of GRP94, a homologue of Hsp90 that is localized to the endoplasmic recticulum. Through GRP94 inhibition, these compounds are likely to manifest anti-cancer, anti-inflammatory, anti-metastasis, and immunosuppressive activities, as well as utility in the treatment of neurodegenerative diseases, and diabetes.
• GRP94 INHIBITORS TO TREAT STEROID-INDUCED OCULAR HYPERTENSIONS AND GLAUCOMAS
  申请人：UNIVERSITY OF SOUTH FLORIDA

  公开号：US20210030719A1

  公开（公告）日：2021-02-04

  A method and composition for preventing, reducing, or treating steroid-induced ocular hypertension and steroid-induced glaucoma using a selective Grp94 inhibitor is presented. The Grp94-selective inhibitor can include methyl 2-(2-(1(4-bromobenzyl)-1H-imidazol-2-yl)ethyl)-3-chloro-4,6-dihydroxybenzoate (4-Br—BnIm) or a derivative thereof. The Grp94-selective inhibitor can be administered prior to, during, or after administration of a steroid to the patient.