3-(N-(4-chlorophenyl)sulfamoyl)-4-methoxybenzoic acid | 312503-89-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(N-(4-chlorophenyl)sulfamoyl)-4-methoxybenzoic acid
• 英文别名: 3-[(4-Chlorophenyl)sulfamoyl]-4-methoxybenzoic acid
• CAS: 312503-89-2
• 化学式: C₁₄H₁₂ClNO₅S
• mdl: MFCD01460818
• 分子量: 341.772
• InChiKey: ZWCKHUIIAOEIOY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  101
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(N-(4-chlorophenyl)sulfamoyl)-4-methoxybenzoic acid 、 对氯苯胺 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 生成 N-(4-chlorophenyl)-3-[(4-chlorophenyl)sulfamoyl]-4-methoxybenzamide
  参考文献：
  名称：

  Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors

  摘要：

  Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in alpha-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.02.003
• 作为产物：
  描述：

  3-氯磺酰基-4-甲氧基苯甲酸 、 对氯苯胺 在 吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 生成 3-(N-(4-chlorophenyl)sulfamoyl)-4-methoxybenzoic acid
  参考文献：
  名称：

  发现和体外优化3-氨磺酰基苯甲酰胺作为ROMK抑制剂

  摘要：

  肾外髓质钾通道（ROMK）抑制剂有望作为新型机制利尿剂，与目前的噻嗪类和loop利尿剂相比，利尿剂引起的低钾血症的风险可能更低。在这里，我们报告的新型3-氨磺酰苯甲酰胺ROMK抑制剂的鉴定。从HTS 4开始，对该系列进行了优化，以为ROMK抑制剂提供良好的体外效能和均衡的ADME谱。与先前报道的小分子ROMK抑制剂相反，该系列成员被证明对人类的抑制作用高于对大鼠ROMK的抑制作用，并且对消除先前报道的ROMK抑制剂的抑制活性的N171D孔突变不敏感。

  DOI：

  10.1021/acsmedchemlett.7b00481

文献信息

• Development and characterization of 3-(benzylsulfonamido)benzamides as potent and selective SIRT2 inhibitors
  作者：Mohammad A. Khanfar、Luisa Quinti、Hua Wang、Soo Hyuk Choi、Aleksey G. Kazantsev、Richard B. Silverman

  DOI：10.1016/j.ejmech.2014.02.003

  日期：2014.4

  Inhibitors of sirtuin-2 deacetylase (SIRT2) have been shown to be protective in various models of Huntington's disease (HD) by decreasing polyglutamine aggregation, a hallmark of HD pathology. The present study was directed at optimizing the potency of SIRT2 inhibitors containing the neuroprotective sulfobenzoic acid scaffold and improving their pharmacology. To achieve that goal, 176 analogues were designed, synthesized, and tested in deacetylation assays against the activities of major human sirtuins SIRT1-3. This screen yielded 15 compounds with enhanced potency for SIRT2 inhibition and 11 compounds having SIRT2 inhibition equal to reference compound AK-1. The newly synthesized compounds also demonstrated higher SIRT2 selectivity over SIRT1 and SIRT3. These candidates were subjected to a dose-response bioactivity assay, measuring an increase in alpha-tubulin K40 acetylation in two neuronal cell lines, which yielded five compounds bioactive in both cell lines and eight compounds bioactive in at least one of the cell lines tested. These bioactive compounds were subsequently tested in a tertiary polyglutamine aggregation assay, which identified five inhibitors. ADME properties of the bioactive SIRT2 inhibitors were assessed, which revealed a significant improvement of the pharmacological properties of the new entities, reaching closer to the goal of a clinically-viable candidate. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Discovery and in Vitro Optimization of 3-Sulfamoylbenzamides as ROMK Inhibitors
  作者：Matthew F. Sammons、Sujay V. Kharade、Kevin J. Filipski、Markus Boehm、Aaron C. Smith、Andre Shavnya、Dilinie P. Fernando、Matthew S. Dowling、Philip A. Carpino、Neil A. Castle、Shannon G. Zellmer、Brett M. Antonio、James R. Gosset、Anthony Carlo、Jerod S. Denton

  DOI：10.1021/acsmedchemlett.7b00481

  日期：2018.2.8

  Inhibitors of the renal outer medullary potassium channel (ROMK) show promise as novel mechanism diuretics, with potentially lower risk of diuretic-induced hypokalemia relative to current thiazide and loop diuretics. Here, we report the identification of a novel series of 3-sulfamoylbenzamide ROMK inhibitors. Starting from HTS hit 4, this series was optimized to provide ROMK inhibitors with good in

  肾外髓质钾通道（ROMK）抑制剂有望作为新型机制利尿剂，与目前的噻嗪类和loop利尿剂相比，利尿剂引起的低钾血症的风险可能更低。在这里，我们报告的新型3-氨磺酰苯甲酰胺ROMK抑制剂的鉴定。从HTS 4开始，对该系列进行了优化，以为ROMK抑制剂提供良好的体外效能和均衡的ADME谱。与先前报道的小分子ROMK抑制剂相反，该系列成员被证明对人类的抑制作用高于对大鼠ROMK的抑制作用，并且对消除先前报道的ROMK抑制剂的抑制活性的N171D孔突变不敏感。