(3S)-1-[4-[(2,3,5,6-tetramethylphenyl)sulfonylamino]-1-naphthyl] pyrrolidine-3-carboxylic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: (3S)-1-[4-[(2,3,5,6-tetramethylphenyl)sulfonylamino]-1-naphthyl] pyrrolidine-3-carboxylic acid
• 英文别名: (3s)-1-(4-{[(2,3,5,6-Tetramethylphenyl)sulfonyl]amino}naphthalen-1-Yl)pyrrolidine-3-Carboxylic Acid；(3S)-1-[4-[(2,3,5,6-tetramethylphenyl)sulfonylamino]naphthalen-1-yl]pyrrolidine-3-carboxylic acid
• 化学式: C₂₅H₂₈N₂O₄S
• 分子量: 452.574
• InChiKey: BVYWIQHJXAEJOD-IBGZPJMESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  95.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  1-氨基-4-硝基萘 在 吡啶 、 copper(l) iodide 、 亚硝酸特丁酯 、 palladium 10% on activated carbon 、 camphor-10-sulfonic acid 、 四丁基溴化铵 、 氢气 、 potassium carbonate 、 copper(ll) bromide 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 20.0~150.0 ℃ 、200.0 kPa 条件下， 反应 64.0h， 生成 (3S)-1-[4-[(2,3,5,6-tetramethylphenyl)sulfonylamino]-1-naphthyl] pyrrolidine-3-carboxylic acid
  参考文献：
  名称：

  A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity

  摘要：

  Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.

  DOI：

  10.1021/acs.jmedchem.9b00723

文献信息

• Naphthyl Sulfonamide Pyrrolidine Derivatives as KEAP-1 Modulators for the Treatment of Diabetes, Obesity, Dyslipidemia and Related Disorders
  申请人：SANOFI

  公开号：EP2997966A1

  公开（公告）日：2016-03-23

  The present invention relates to naphthyl sulfonamide pyrrolidine derivatives of the formula I in which R1, R2, R3, R4, R5, R6, R7, R10, A, D, q, i, n, m, L and R50 are defined as indicated below. The naphthyl sulfonamide pyrrolidine derivatives I are KEAP-1 modulators and useful for the prevention and/or treatment of diabetes, obesity, dyslipidemia and related disorders. The invention furthermore relates to the use of naphthyl sulfonamide pyrrolidine derivatives of the formula I as active ingredients in pharmaceuticals, and pharmaceutical compositions comprising them.

  本发明涉及公式I的萘磺酰胺吡咯烷衍生物，其中R1、R2、R3、R4、R5、R6、R7、R10、A、D、q、i、n、m、L和R50的定义如下所示。 萘磺酰胺吡咯烷衍生物I是KEAP-1调节剂，可用于预防和/或治疗糖尿病、肥胖、血脂异常及相关疾病。 本发明还涉及将公式I的萘磺酰胺吡咯烷衍生物用作药物中的活性成分，以及包含它们的药物组合物。
• WO2022272133A2
  申请人：——

  公开号：WO2022272133A2

  公开（公告）日：2022-12-29
• A Comparative Assessment Study of Known Small-Molecule Keap1−Nrf2 Protein–Protein Interaction Inhibitors: Chemical Synthesis, Binding Properties, and Cellular Activity
  作者：Kim T. Tran、Jakob S. Pallesen、Sara M. Ø. Solbak、Dilip Narayanan、Amina Baig、Jie Zang、Alejandro Aguayo-Orozco、Rosa M. C. Carmona、Anthony D. Garcia、Anders Bach

  DOI：10.1021/acs.jmedchem.9b00723

  日期：2019.9.12

  Inhibiting the protein-protein interaction (PPI) between the transcription factor Nrf2 and its repressor protein Keap1 has emerged as a promising strategy to target oxidative stress in diseases, including central nervous system (CNS) disorders. Numerous non-covalent small-molecule Keap1-Nrf2 PPI inhibitors have been reported to date, but many feature suboptimal physicochemical properties for permeating the blood brain barrier, while others contain problematic structural moieties. Here, we present the first side-by-side assessment of all reported Keap1-Nrf2 PPI inhibitor classes using fluorescence polarization, thermal shift assay, and surface plasmon resonance-and further evaluate the compounds in an NQO1 induction cell assay and in counter tests for nonspecific activities. Surprisingly, half of the compounds were inactive or deviated substantially from reported activities, while we confirm the cross-assay activities for others. Through this study, we have identified the most promising Keap1-Nrf2 inhibitors that can serve as pharmacological probes or starting points for developing CNS-active Keap1 inhibitors.