4-(4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol | 394237-61-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol
• 英文别名: 4-[4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl]benzene-1,3-diol
• CAS: 394237-61-7
• 化学式: C₁₇H₁₆N₂O₃
• 分子量: 296.326
• InChiKey: GSBFARPNIZUMHA-UHFFFAOYSA-N

物化性质

• 沸点：
  508.1±50.0 °C(Predicted)
• 密度：
  1.295±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：250 mg/mL（843.68 mM）

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  78.4
• 氢给体数：
  3
• 氢受体数：
  4

制备方法与用途

生物活性

M77976 是一种特异性的，ATP 竞争性的丙酮酸脱氢酶激酶 PDK4 抑制剂，其作用的 IC50 值为 648 μM。M77976 有用于肥胖症和糖尿病研究的潜力。

靶点

IC50: 648 μM (PDK4)

体外研究

M77976 binds to the ATP-binding pocket of PDK4 and causes local conformational changes with complete disordering of the ATP lid.
M77976 makes hydrophobic interactions with the side chains of Asn258, Ala262, Val298, Leu306 and Thr358 of PDK4.

反应信息

• 作为反应物：
  描述：

  4-(4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol 在 benzyltrimethylazanium tribroman-2-uide 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以47%的产率得到4-Bromo-6-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol
  参考文献：
  名称：

  Novel, Potent Small-Molecule Inhibitors of the Molecular Chaperone Hsp90 Discovered through Structure-Based Design

  摘要：

  The crystal structure of a previously reported screening hit 1 (CCT018159) bound to the N terminal domain of molecular chaperone Hsp90 has been used to design 5-amide analogues. These exhibit enhanced potency against the target in binding and functional assays with accompanying appropriate cellular pharmaeodynamic changes. Compound 11 (VER-49009) compares favorably with the clinically evaluated 17-AAG.

  DOI：

  10.1021/jm050355z
• 作为产物：
  描述：

  间苯二酚 在 三氟化硼乙醚 、 potassium carbonate 、 一水合肼 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成 4-(4-(4-methoxyphenyl)-5-methyl-1H-pyrazol-3-yl)benzene-1,3-diol
  参考文献：
  名称：

  Repurposing Hsp90 inhibitors as antibiotics targeting histidine kinases

  摘要：

  To address the growing need for new antimicrobial agents, we explored whether inhibition of bacterial signaling machinery could inhibit bacterial growth. Because bacteria rely on two-component signaling systems to respond to environmental changes, and because these systems are both highly conserved and mediated by histidine kinases, inhibiting histidine kinases may provide broad spectrum antimicrobial activity. The histidine kinase ATP binding domain is conserved with the ATPase domain of eukaryotic Hsp90 molecular chaperones. To find a chemical scaffold for compounds that target histidine kinases, we leveraged this conservation. We screened ATP competitive Hsp90 inhibitors against CckA, an essential histidine kinase in Caulobacter crescentus that controls cell growth, and showed that the diaryl pyrazole is a promising scaffold for histidine kinase inhibition. We synthesized a panel of derivatives and found that they inhibit the histidine kinases C. crescentus CckA and Salmonella PhoQ but not C. crescentus DivJ; and they inhibit bacterial growth in both Gram-negative and Gram-positive bacterial strains. (C) 2017 The Authors. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2017.10.036

文献信息

• 7-Hydroxy-benzopyran-4-one Derivatives: A Novel Pharmacophore of Peroxisome Proliferator-Activated Receptor α and -γ (PPARα and γ) Dual Agonists
  作者：Azadeh Matin、Navnath Gavande、Moon S. Kim、Nancy X. Yang、Noeris K. Salam、Jane R. Hanrahan、Rebecca H. Roubin、David E. Hibbs

  DOI：10.1021/jm900964r

  日期：2009.11.12

  Design, synthesis, and in vitro bioevaluation of a new class of potential dual PPARα and γ agonists discovered through a structure-driven design paradigm are described. The 7-hydroxy-benzopyran-4-one moiety (includes flavones, flavanones, and isoflavones) is the key pharmacophore of these novel molecules, exhibiting similarity to the core structure of both fibrates and thiazolidinediones. New lead

  描述了通过结构驱动设计范式发现的新型潜在的双重PPARα和γ双重激动剂的设计，合成和体外生物评价。7-羟基-苯并吡喃-4-酮部分（包括黄酮，黄烷酮和异黄酮）是这些新分子的关键药效​​基团，与贝特类药物和噻唑烷二酮的核心结构相似。从“保健食品”和合成类似物中鉴定出新的PPAR配体。总共筛选了77个分子，包括查耳酮，黄酮，黄烷酮，异黄酮和吡唑衍生物，并进行了双重激动剂的构效关系研究。化合物68，70，72，和76被鉴定为新型有效的PPARα和γ双重激动剂。这些新型分子可能会成为PPAR相关疾病（包括II型糖尿病和代谢综合征）未来的领先者。
• GLUCOKINASE ACTIVATORS
  申请人：Cao X. Sheldon

  公开号：US20070197532A1

  公开（公告）日：2007-08-23

  Compounds, pharmaceutical compositions, kits and methods are provided for use with glucokinase that comprise a compound selected from the group consisting of: wherein the variables are as defined herein.

  提供了用于与葡萄糖激酶一起使用的化合物、药物组合物、试剂盒和方法，其中包括从以下组中选择的化合物：其中变量如本文所定义。
• [EN] 3,4-DIARYLPYRAZOLES AND THEIR USE IN THE THERAPY OF CANCER<br/>[FR] 3,4-DIARYLPYRAZOLES ET LEUR UTILISATION EN THERAPIE ANTI-CNCEREUSE
  申请人：RIBOTARGETS LTD

  公开号：WO2003055860A1

  公开（公告）日：2003-07-10

  The present invention pertains to the use of certain 3,4-diarylpyrazoles of formula (I), both in vitro and in vivo, to inhibit heat shock protein 90 (HSP90), and in the treatment of conditions mediated by HSP90, including, for example, cancer; wherein: Ar3 is independently: a C5-20aryl group, and is optionally substituted; Ar4 is independently: a C5-20aryl group, and is optionally substituted; R5 is independently: hydrogen; halo; hydroxy; ether; formyl; acyl; carboxy; ester; acyloxy; oxycarbonyloxy; amido; acylamido; aminocarbonyloxy; tetrazolyl; amino; nitro; cyano; azido; sulfhydryl; thioether; sulfonamido; C1-7alkyl; C3-20heterocycyl; or C5-20aryl; RN is independently: -H; C1-7alkyl; C3-20heterocycyl; or, C5-20aryl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to such compounds, pharmaceutical compositions comprising such compounds, such compounds for medical use, such compounds for use in the treatment of conditions mediated by HSP90, including, for example, cancer, and use of such compounds in the preparation of medicaments for such treatments.

  本发明涉及使用式(I)的特定3,4-二芳基吡唑化合物，无论是体外还是体内，以抑制热休克蛋白90（HSP90）的作用，并用于治疗由HSP90介导的疾病，例如癌症；其中：Ar3独立地表示：C5-20芳基基团，且可选地被取代；Ar4独立地表示：C5-20芳基基团，且可选地被取代；R5独立地表示：氢；卤素；羟基；醚；甲酰基；酰基；羧基；酯基；酰氧基；氧羰基氧基；酰胺基；酰胺氧基；氨基羰氧基；四唑基；氨基；硝基；氰基；偶氮基；硫醇基；硫醚基；磺酰胺基；C1-7烷基；C3-20杂环基；或C5-20芳基；RN独立地表示：-H；C1-7烷基；C3-20杂环基；或C5-20芳基；以及其药学上可接受的盐，溶剂化合物，酰胺，酯，醚，化学保护形式和前药。本发明还涉及这些化合物，包含这些化合物的制药组合物，用于医疗用途的这些化合物，用于治疗由HSP90介导的疾病，例如癌症的这些化合物，以及使用这些化合物制备此类治疗药物的用途。
• 3,4-diarylpyrazoles and their use in the therapy of cancer
  申请人：Drysdale James Martin

  公开号：US20050222230A1

  公开（公告）日：2005-10-06

  The present invention pertains to the use of certain 3,4-diarylpyrazoles of formula (I), both in vitro and in vivo, to inhibit heat shock protein 90 (HSP90), and in the treatment of conditions mediated by HSP90, including, for example, cancer; wherein: Ar 3 is independently: a C 5-20 aryl group, and is optionally substituted; Ar 4 is independently: a C 5-20 aryl group, and is optionally substituted; R 5 is independently: hydrogen; halo; hydroxy; ether; formyl; acyl; carboxy; ester, acyloxy; oxycarbonyloxy; amido; acylamido; aminocarbonyloxy; tetrazolyl; amino; nitro; cyano; azido; sulfhydryl; thioether; sulfonamido; C 1-7 alkyl; C 3-20 heterocycyl; or C 5-20 aryl; RN is independently: —H; C 1-7 alkyl; C 3-20 heterocycyl; or, C 5-20 aryl; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms, and prodrugs thereof. The present invention also pertains to such compounds, pharmaceutical compositions comprising such compounds, such compounds for medical use, such compounds for use in the treatment of conditions mediated by HSP90, including, for example, cancer, and use of such compounds in the preparation of medicaments for such treatments.

  本发明涉及使用公式（I）中的某些3,4-二芳基吡唑化合物，无论是在体内还是体外，用于抑制热休克蛋白90（HSP90），以及用于治疗由HSP90介导的疾病，包括癌症等；其中：Ar3独立地表示：C5-20芳基基团，可选地取代；Ar4独立地表示：C5-20芳基基团，可选地取代；R5独立地表示：氢；卤素；羟基；醚；甲酰基；酰基；羧基；酯，酰氧基；氧羰酰氧基；酰胺；酰胺基；氨基羰酰氧基；四唑基；氨基；硝基；氰基；偶氮基；磺酰基；硫醚基；磺酰胺基；C1-7烷基；C3-20杂环基；或C5-20芳基；R N 独立地表示：-H；C1-7烷基；C3-20杂环基；或C5-20芳基；以及其药学上可接受的盐，溶剂化合物，酰胺，酯，醚，化学保护形式和前药。本发明还涉及这种化合物，包含这种化合物的制药组合物，用于医学用途的这种化合物，用于治疗由HSP90介导的疾病，包括癌症的这种化合物，以及使用这种化合物制备这种治疗药物的用途。
• 3,4-DIARYLPYRAZOLES AND THEIR USE IN THE THERAPY OF CANCER
  申请人：Vernalis (Oxford) Ltd

  公开号：EP1456180A1

  公开（公告）日：2004-09-15