2-isobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile | 1352943-58-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-isobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
• 英文别名: 2-Isobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile；2-(2-methylpropoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
• CAS: 1352943-58-8
• 化学式: C₁₇H₂₄BNO₃
• 分子量: 301.193
• InChiKey: YNVHMOXBYDKVHG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.89
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  51.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-isobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile 在 甲醇 、 四(三苯基膦)钯 、 sodium carbonate 、 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 12.0h， 生成 C₁₅H₁₈N₄O₃
  参考文献：
  名称：

  Isocytosine-based inhibitors of xanthine oxidase: Design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia

  摘要：

  Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC50 was obtained in the process. Five most potent compounds with nanomolar IC50 values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.10.029
• 作为产物：
  描述：

  5-溴-2-羟基苯甲腈 在 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 、 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 2-isobutoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile
  参考文献：
  名称：

  HTS，然后进行基于NMR的反向筛选。发现和优化作为黄嘌呤氧化酶可逆和竞争性抑制剂的嘧啶酮

  摘要：

  描述了新型，非嘌呤的黄嘌呤氧化酶抑制剂的鉴定。经过高通量筛选活动后，基于NMR的反筛选用于区分活性物，这些活性物以可逆方式与XO相互作用，与分析伪像分离。该方法将嘧啶酮1鉴定为可逆的竞争性抑制剂，具有良好的铅样性质。导致先头运动获得化合物41，一种hXO的纳摩尔抑制剂，口服给药后在高尿酸血症大鼠模型中具有功效。

  DOI：

  10.1016/j.bmcl.2014.01.050

文献信息

• Lead optimization of isocytosine-derived xanthine oxidase inhibitors
  作者：Komal Bajaj、Sandeep Burudkar、Pranay Shah、Ashish Keche、Usha Ghosh、Prashant Tannu、Smriti Khanna、Ankita Srivastava、Nitin J. Deshmukh、Amol Dixit、Yogesh Ahire、Anagha Damre、Kumar V.S. Nemmani、Asha Kulkarni-Almeida、Chandrika B-Rao、Rajiv Sharma、H. Sivaramakrishnan

  DOI：10.1016/j.bmcl.2012.11.057

  日期：2013.2

  We report our attempts at improving the oral efficacy of low-nanomolar inhibitors of xanthine oxidase from isocytosine series through chemical modifications. Our lead compound had earlier shown good in vivo efficacy when administered intraperitoneally but not orally. Several modifications are reported here which achieved more than twofold improvement in exposure. A compound with significant improvement in oral efficacy was also obtained. (c) 2012 Elsevier Ltd. All rights reserved.
• HTS followed by NMR based counterscreening. Discovery and optimization of pyrimidones as reversible and competitive inhibitors of xanthine oxidase
  作者：Johan Evenäs、Fredrik Edfeldt、Matti Lepistö、Naila Svitacheva、Anna Synnergren、Britta Lundquist、Mia Gränse、Anna Rönnholm、Mikael Varga、John Wright、Min Wei、Sherrie Yue、Junfeng Wang、Chong Li、Xuan Li、Gang Chen、Yong Liao、Gang Lv、Ann Tjörnebo、Frank Narjes

  DOI：10.1016/j.bmcl.2014.01.050

  日期：2014.3

  based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO

  描述了新型，非嘌呤的黄嘌呤氧化酶抑制剂的鉴定。经过高通量筛选活动后，基于NMR的反筛选用于区分活性物，这些活性物以可逆方式与XO相互作用，与分析伪像分离。该方法将嘧啶酮1鉴定为可逆的竞争性抑制剂，具有良好的铅样性质。导致先头运动获得化合物41，一种hXO的纳摩尔抑制剂，口服给药后在高尿酸血症大鼠模型中具有功效。
• Isocytosine-based inhibitors of xanthine oxidase: Design, synthesis, SAR, PK and in vivo efficacy in rat model of hyperuricemia
  作者：Smriti Khanna、Sandeep Burudkar、Komal Bajaj、Pranay Shah、Ashish Keche、Usha Ghosh、Avani Desai、Ankita Srivastava、Asha Kulkarni-Almeida、Nitin J. Deshmukh、Amol Dixit、Manoja K. Brahma、Umakant Bahirat、Lalit Doshi、Kumar V.S. Nemmani、Prashant Tannu、Anagha Damre、Chandrika B-Rao、Rajiv Sharma、H. Sivaramakrishnan

  DOI：10.1016/j.bmcl.2012.10.029

  日期：2012.12

  Structure-activity relationship studies were carried out for lead generation following structure-guided design approach from an isocytosine scaffold identified earlier for xanthine oxidase inhibition. A 470-fold improvement in in vitro IC50 was obtained in the process. Five most potent compounds with nanomolar IC50 values were selected for pharmacokinetics and in vivo experiments. The best compound showed good in vivo activity when administered intraperitoneally but was not active by oral route. The results suggest that improvement in oral exposure could improve the in vivo efficacy of this series. (C) 2012 Elsevier Ltd. All rights reserved.