ethyl 7-hydroxy-3-methyl-1H-indazole-5-carboxylate | 187034-05-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 英文名称: ethyl 7-hydroxy-3-methyl-1H-indazole-5-carboxylate
• 英文别名: ethyl 3-methyl-7-hydroxy-1H-indazole-5-carboxylate；ethyl 7-hydroxy-3-methyl-2H-indazole-5-carboxylate
• CAS: 187034-05-5
• 化学式: C₁₁H₁₂N₂O₃
• 分子量: 220.228
• InChiKey: BGAHIKSYHSNRBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  75.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 7-hydroxy-3-methyl-1H-indazole-5-carboxylate 在 N-甲基吗啉 、 2-氯-4,6-二甲氧基-1,3,5-三嗪 、 sodium hydride 、 lithium hydroxide 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 2.0h， 生成 1-(7-ethoxy-3-methyl-1H-indazole-5-carbonyl)-2'-ethyl-3'-methyl-2'H-spiro[piperidine-4,5'-pyrano[3,2-c]pyrazol]-7'(6'H)-one
  参考文献：
  名称：

  Maximizing Lipophilic Efficiency: The Use of Free-Wilson Analysis in the Design of Inhibitors of Acetyl-CoA Carboxylase

  摘要：

  This paper describes the design and synthesis of a novel series of dual inhibitors of acetyl-CoA carboxylase 1 and 2 (ACC1 and ACC2). Key findings include the discovery of an initial lead that was modestly potent and subsequent medicinal chemistry optimization with a focus on lipophilic efficiency (LipE) to balance overall druglike properties. Free-Wilson methodology provided a clear breakdown of the contributions of specific structural elements to the overall LipE, a rationale for prioritization of virtual compounds for synthesis, and a highly successful prediction of the LipE of the resulting analogues. Further preclinical assays, including in vivo malonyl-CoA reduction in both rat liver (ACC1) and rat muscle (ACC2), identified an advanced analogue that progressed to regulatory toxicity studies.

  DOI：

  10.1021/jm201503u
• 作为产物：
  描述：

  3-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-4-yl)but-3-enoic acid 在 sodium acetate 、 乙酸酐 、 碳酸氢钠 作用下， 以 水 为溶剂， 以40%的产率得到ethyl 7-hydroxy-3-methyl-1H-indazole-5-carboxylate
  参考文献：
  名称：

  [EN] PYRAZOLOSPIROKETONE ACETYL-C0A CARBOXYLASE INHIBITORS
  [FR] INHIBITEURS DE LA PYRAZOLOSPIROCÉTONE ACÉTL-COA CARBOXYLASE

  摘要：

  本发明提供了式(1)的化合物或所述化合物的药用可接受盐，其中R1、R2和R3如本文所述；其药物组合物；以及用于治疗通过抑制动物中的乙酰辅酶A羧化酶酶活性来调节的疾病、病症或障碍的使用方法。

  公开号：

  WO2009144554A1

文献信息

• Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models
  作者：Jon J. Winter-Holt、Catherine Bardelle、Elisabetta Chiarparin、Ian L. Dale、Paul R. J. Davey、Nichola L. Davies、Christopher Denz、Shaun M. Fillery、Carine M. Guérot、Fujin Han、Samantha J. Hughes、Meghana Kulkarni、Zhaoqun Liu、Alexander Milbradt、Thomas A. Moss、Huijun Niu、Joe Patel、Alfred A. Rabow、Marianne Schimpl、Junjie Shi、Dongqing Sun、Dejian Yang、Sylvie Guichard

  DOI：10.1021/acs.jmedchem.1c01871

  日期：2022.2.24

  several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the

  ATAD2 是一种表观遗传的含溴结构域的靶标，在许多癌症中过度表达，并已被建议作为潜在的肿瘤学靶标。虽然文献中已经描述了几种小分子抑制剂，但它们的细胞活性已被证明是平淡无奇的。在这项工作中，我们描述了通过高通量筛选鉴定一系列新的 ATAD2 抑制剂，确认溴域区域作为作用位点，以及为提高初始命中的效力、选择性和渗透性而进行的优化活动。结果是化合物5 (AZ13824374)，一种高效和选择性的 ATAD2 抑制剂，在一系列乳腺癌模型中显示出细胞靶标参与和抗增殖活性。
• Pyrazolospiroketone acetyl-CoA carboxylase inhibitors
  申请人：Pfizer Inc.

  公开号：US08318762B2

  公开（公告）日：2012-11-27

  The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R1, R2, and R3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) in an animal.

  本发明提供了公式（1）的化合物或其药学上可接受的盐，其中R1、R2和R3如本文所述；其制备的药物组合物；以及在动物体内抑制乙酰辅酶A羧化酶酶（s）的作用下调节的疾病、状况或疾患的治疗中使用它们的方法。
• Pyrazolospiroketone Acetyl-CoA Carboxylase Inhibitors
  申请人：Corbett Jeffrey W.

  公开号：US20110028390A1

  公开（公告）日：2011-02-03

  The invention provides compounds of Formula (1) or a pharmaceutically acceptable salt of said compound, wherein R 1 , R 2 , and R 3 are as described herein; pharmaceutical compositions thereof; and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of acetyl-CoA carboxylase enzyme(s) in an animal.

  本发明提供公式（1）的化合物或其药学上可接受的盐，其中R1，R2和R3如本文所述；其药物组合物；以及将其用于治疗动物中受乙酰辅酶A羧化酶酶抑制调节的疾病，状况或障碍。
• PYRAZOLOSPIROKETONE ACETYL-C0A CARBOXYLASE INHIBITORS
  申请人：Pfizer Inc.

  公开号：EP2297163A1

  公开（公告）日：2011-03-23
• US8318762B2
  申请人：——

  公开号：US8318762B2

  公开（公告）日：2012-11-27