2-(benzo[d][1,3]dioxol-5-ylamino)thiazole-4-carboxylic acid | 1176121-35-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并间二氧杂环戊烯类
• 英文名称: 2-(benzo[d][1,3]dioxol-5-ylamino)thiazole-4-carboxylic acid
• 英文别名: 2-(1,3-benzodioxol-5-ylamino)-1,3-thiazole-4-carboxylic acid；2-(1,3-Benzodioxol-5-ylamino)-1,3-thiazole-4-carboxylic acid
• CAS: 1176121-35-9
• 化学式: C₁₁H₈N₂O₄S
• 分子量: 264.262
• InChiKey: VQCAJURUVLTENR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  109
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  N-(3-氨丙基)吗啉 、 2-(benzo[d][1,3]dioxol-5-ylamino)thiazole-4-carboxylic acid 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 10.17h， 以89%的产率得到N-(3-morpholinopropyl) 2-(benzo[d][1,3]dioxol-5-ylamino)thiazole-4-carboxamide
  参考文献：
  名称：

  在甲型流感病毒核蛋白三聚化过程中破坏保守的盐桥。

  摘要：

  流感感染中的抗病毒药物耐药性已成为对公共卫生的主要威胁。为了开发广谱的流感抑制剂来解决耐药性问题，我们之前确定了高度保守的核蛋白三聚体E339 ... R416盐桥为靶标，化合物1为通过EC50破坏盐桥的抑制剂甲型流感病毒= 2.7μM（A / WSN / 1933）。我们通过基于结构的方法进一步修饰了该化合物，并进行了抗病毒活性筛选，以鉴定化合物29和30的EC50值分别为110和120 nM，并且没有可测量的宿主细胞毒性。与临床使用的神经氨酸酶抑制剂相比，这两种化合物对耐药性A型流感病毒株和B型流感病毒显示出更好的活性，

  DOI：

  10.1021/acs.jmedchem.9b01244
• 作为产物：
  描述：

  ethyl 2-(benzo[d][1,3]dioxolane-5-yl-amino)thiazole-4-carboxylate 在 乙醇 、 sodium hydroxide 作用下， 生成 2-(benzo[d][1,3]dioxol-5-ylamino)thiazole-4-carboxylic acid
  参考文献：
  名称：

  The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore

  摘要：

  Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease. Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2013.06.047

文献信息

• [EN] COMPOUNDS<br/>[FR] COMPOSÉS
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2012037351A1

  公开（公告）日：2012-03-22

  Compounds, pharmaceutical compositions containing them, and their use treatment of conditions mediated by the TRPC3 and/or TRPC6 ion channels.

  化合物，含有它们的制药组合物，以及它们用于治疗由TRPC3和/或TRPC6离子通道介导的疾病的用途。
• Disrupting the Conserved Salt Bridge in the Trimerization of Influenza A Nucleoprotein
  作者：Jennifer L. Woodring、Shao-Hung Lu、Larissa Krasnova、Shih-Chi Wang、Jhih-Bin Chen、Chiu-Chun Chou、Yi-Chou Huang、Ting-Jen Rachel Cheng、Ying-Ta Wu、Yu-Hou Chen、Jim-Min Fang、Ming-Daw Tsai、Chi-Huey Wong

  DOI：10.1021/acs.jmedchem.9b01244

  日期：2020.1.9

  threat to public health. To develop a broad-spectrum inhibitor of influenza to combat the problem of drug resistance, we previously identified the highly conserved E339...R416 salt bridge of the nucleoprotein trimer as a target and compound 1 as an inhibitor disrupting the salt bridge with an EC50 = 2.7 μM against influenza A (A/WSN/1933). We have further modified this compound via a structure-based

  流感感染中的抗病毒药物耐药性已成为对公共卫生的主要威胁。为了开发广谱的流感抑制剂来解决耐药性问题，我们之前确定了高度保守的核蛋白三聚体E339 ... R416盐桥为靶标，化合物1为通过EC50破坏盐桥的抑制剂甲型流感病毒= 2.7μM（A / WSN / 1933）。我们通过基于结构的方法进一步修饰了该化合物，并进行了抗病毒活性筛选，以鉴定化合物29和30的EC50值分别为110和120 nM，并且没有可测量的宿主细胞毒性。与临床使用的神经氨酸酶抑制剂相比，这两种化合物对耐药性A型流感病毒株和B型流感病毒显示出更好的活性，
• The discovery of potent blockers of the canonical transient receptor channels, TRPC3 and TRPC6, based on an anilino-thiazole pharmacophore
  作者：David G. Washburn、Dennis A. Holt、Jason Dodson、Jeff J. McAtee、Lamont R. Terrell、Linda Barton、Sharada Manns、Anna Waszkiewicz、Christina Pritchard、Dan J. Gillie、Dwight M. Morrow、Elizabeth A. Davenport、Irina M. Lozinskaya、Jeffrey Guss、Jonathan B. Basilla、Lorena Kallal Negron、Michael Klein、Robert N. Willette、Rusty E. Fries、Timothy C. Jensen、Xiaoping Xu、Christine G. Schnackenberg、Joseph P. Marino

  DOI：10.1016/j.bmcl.2013.06.047

  日期：2013.9

  Lead optimization of piperidine amide HTS hits, based on an anilino-thiazole core, led to the identification of analogs which displayed low nanomolar blocking activity at the canonical transient receptor channels 3 and 6 (TRPC3 & 6) based on FLIPR (carbachol stimulated) and electrophysiology (OAG stimulated) assays. In addition, the anilino-thiazole amides displayed good selectivity over other TRP channels (TRPA1, TRPV1, and TRPV4), as well as against cardiac ion channels (CaV1.2, hERG, and NaV1.5). The high oxidation potential of the aliphatic piperidine and aniline groups, as well as the lability of the thiazole amide group contributed to the high clearance observed for this class of compounds. Conversion of an isoquinoline amide to a naphthyridine amide markedly reduced clearance for the bicyclic piperidines, and improved oral bioavailability for this compound series, however TRPC3 and TRPC6 blocking activity was reduced substantially. Although the most potent anilino-thiazole amides ultimately lacked oral exposure in rodents and were not suitable for chronic dosing, analogs such as 14-19, 22, and 23 are potentially valuable in vitro tool compounds for investigating the role of TRPC3 and TRPC6 in cardiovascular disease. Published by Elsevier Ltd.