3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-4-methoxybenzoic acid | 1586822-29-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-4-methoxybenzoic acid
• 英文别名: 3-[(4-Acetylphenyl)-methylsulfamoyl]-4-methoxybenzoic acid；3-[(4-acetylphenyl)-methylsulfamoyl]-4-methoxybenzoic acid
• CAS: 1586822-29-8
• 化学式: C₁₇H₁₇NO₆S
• 分子量: 363.391
• InChiKey: MDOVKZOZIHJJQF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  109
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-4-methoxybenzoic acid 、 对氨基苯腈 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， 以71%的产率得到3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-N-(4-cyanophenyl)-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：

  大茴香酸 在 吡啶 作用下， 以 乙酸乙酯 为溶剂， 反应 4.0h， 生成 3-(N-(4-acetylphenyl)-N-methylsulfamoyl)-4-methoxybenzoic acid
  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

文献信息

• Benzamide Compounds and Related Methods of Use
  申请人：Northwestern University

  公开号：US20150025235A1

  公开（公告）日：2015-01-22

  Benzamide compounds and derivatives thereof, as can be used for selective inhibition of the SIRT2 enzyme and/or therapeutic use in the treatment of Huntington's disease.

  苯甲酰胺化合物及其衍生物可用于选择性抑制SIRT2酶和/或治疗亨廷顿病。
• US9371277B2
  申请人：——

  公开号：US9371277B2

  公开（公告）日：2016-06-21
• US9533947B2
  申请人：——

  公开号：US9533947B2

  公开（公告）日：2017-01-03
• US9890117B2
  申请人：——

  公开号：US9890117B2

  公开（公告）日：2018-02-13
• 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.