2-[[(tert-butyloxy)carbonyl]-amino]-4-phenyl-1,3-thiazole-5-carboxylic acid | 302963-99-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 2-[[(tert-butyloxy)carbonyl]-amino]-4-phenyl-1,3-thiazole-5-carboxylic acid
• 英文别名: 2-tert-butoxycarbonyloxyamino-4-phenyl-thiazole-5-carboxylic acid；2-((Tert-butoxycarbonyl)amino)-4-phenylthiazole-5-carboxylic acid；2-[(2-methylpropan-2-yl)oxycarbonylamino]-4-phenyl-1,3-thiazole-5-carboxylic acid
• CAS: 302963-99-1
• 化学式: C₁₅H₁₆N₂O₄S
• 分子量: 320.369
• InChiKey: MOQZNNDIUAAZES-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  117
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-[[(tert-butyloxy)carbonyl]-amino]-4-phenyl-1,3-thiazole-5-carboxylic acid 在 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 30.08h， 生成 2-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,4-diphenylthiazole-5-carboxamide
  参考文献：
  名称：

  Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays

  摘要：

  Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

  DOI：

  10.1016/j.ejmech.2020.112833
• 作为产物：
  描述：

  碳酸二叔丁酯 在 4-二甲氨基吡啶 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 为溶剂， 反应 8.0h， 生成 2-[[(tert-butyloxy)carbonyl]-amino]-4-phenyl-1,3-thiazole-5-carboxylic acid
  参考文献：
  名称：

  Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays

  摘要：

  Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.

  DOI：

  10.1016/j.ejmech.2020.112833

文献信息

• Cyclic protein tyrosine kinase inhibitors
  申请人：——

  公开号：US20040054186A1

  公开（公告）日：2004-03-18

  Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.

  新型环状化合物及其盐类，含有此类化合物的药物组合物，以及使用此类化合物治疗蛋白质酪氨酸激酶相关疾病，如免疫和肿瘤疾病的方法。
• Discovery and initial SAR of 2-amino-5-carboxamidothiazoles as inhibitors of the Src-family kinase p56Lck
  作者：John Wityak、Jagabandhu Das、Robert V. Moquin、Zhongqi Shen、James Lin、Ping Chen、Arthur M. Doweyko、Sidney Pitt、Suhong Pang、Ding Ren Shen、Qiong Fang、Henry F. de Fex、Gary L. Schieven、Steven B. Kanner、Joel C. Barrish

  DOI：10.1016/j.bmcl.2003.08.054

  日期：2003.11

  A novel series of 2-amino-5-5carboxamidothiazoles were identified as inhibitors of Lck. Structure-activity studies demonstrate the structural requirements for potent Lck activity. Cyclopropylamide 11d is a potent Lck inhibitor having submicromolar activity in a PBL proliferation assay. (C) 2003 Elsevier Ltd. All rights reserved.
• Discovery of novel VX-809 hybrid derivatives as F508del-CFTR correctors by molecular modeling, chemical synthesis and biological assays
  作者：Alice Parodi、Giada Righetti、Emanuela Pesce、Annalisa Salis、Bruno Tasso、Chiara Urbinati、Valeria Tomati、Gianluca Damonte、Marco Rusnati、Nicoletta Pedemonte、Elena Cichero、Enrico Millo

  DOI：10.1016/j.ejmech.2020.112833

  日期：2020.12

  Cystic fibrosis (CF) is the autosomal recessive disorder most recurrent in Caucasian populations. It is caused by different mutations in the cystic fibrosis transmembrane regulator protein (CFTR) gene, with F508del being the most common. During the last years, small-molecule therapy chosen to contrast CF relied on compounds that correct CFTR misfolding and ER retention (correctors such as VX-809), or defective channel gating (potentiators such as VX-770). Combination therapy with the two series of drugs has been applied, leading to the approval of several multi-drugs such as Orkambi. Despite this, this treatment proved to be only partially effective making the search for novel modulators an urgent need to contrast CF. Recently, we reported compound 2a as reference compound of a series of aminoarylthiazole-VX-809 hybrid derivatives exhibiting promising F508del-CFTR corrector ability. Herein, we report exploring the docking mode of the prototype VX-809 and of 2a in order to derive useful guidelines for the rational design of novel optimized analogues. To demonstrate experimentally their effective F508del-CFTR-binding and rescuing potential, the most promising derivatives had been synthesized and evaluated in biological assays including YFP functional assay on F508del-CFTR CFBE41o-cells, trans epithelial electrical resistance (TEER) and surface plasmon resonance (SPR). This multidisciplinary strategy led to the discovery of a second series of hybrids including 7j and 7m endowed with higher potency than the prototype.