N-(3,5-bis(trifluoromethyl)benzyl)-N,1-dimethyl-2-oxo-4- (pyrrolidin-1-yl)-1,2-dihydroquinoline-3-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: N-(3,5-bis(trifluoromethyl)benzyl)-N,1-dimethyl-2-oxo-4- (pyrrolidin-1-yl)-1,2-dihydroquinoline-3-carboxamide
• 英文别名: N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N,1-dimethyl-2-oxo-4-pyrrolidin-1-ylquinoline-3-carboxamide
• 化学式: C₂₅H₂₃F₆N₃O₂
• 分子量: 511.467
• InChiKey: MCDADOMPEINVRO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  36
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  43.9
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3,5-双三氟甲基苯基-N-甲基甲胺 在 三乙胺 、 三氯氧磷 作用下， 以 二甲基亚砜 、 甲苯 、 乙腈 为溶剂， 反应 15.0h， 生成 N-(3,5-bis(trifluoromethyl)benzyl)-N,1-dimethyl-2-oxo-4- (pyrrolidin-1-yl)-1,2-dihydroquinoline-3-carboxamide
  参考文献：
  名称：

  发现1,8-萘啶-2-酮衍生物可作为有效的选择性鞘磷脂合成酶2抑制剂。

  摘要：

  鞘磷脂合酶2（SMS2）作为治疗各种心血管疾病和代谢疾病的药物靶标已引起关注。高通量筛选命中2-喹诺酮10的修饰在纳摩尔浓度下增强了对SMS2的抑制，对SMS1具有良好的选择性。为了改善诸如被动膜渗透性和水溶性的药物特性，尝试调节亲脂性，并且将1，8-萘啶-2-酮37鉴定为有效和选择性的SMS2抑制剂。在小鼠中反复治疗后，肝鞘磷脂水平显着降低，表明化合物37可能是一种有效的体内工具，用于阐明SMS2酶的作用并发展针对SMS2相关疾病的治疗方法。

  DOI：

  10.1016/j.bmc.2020.115376

文献信息

• Discovery and characterization of selective human sphingomyelin synthase 2 inhibitors
  作者：Ryutaro Adachi、Kazumasa Ogawa、Shin-ichi Matsumoto、Takuya Satou、Yukiya Tanaka、Jyunichi Sakamoto、Takashi Nakahata、Rei Okamoto、Masahiro Kamaura、Tomohiro Kawamoto

  DOI：10.1016/j.ejmech.2017.04.067

  日期：2017.8

  Sphingomyelin synthase (SMS) is a membrane enzyme that catalyzes the synthesis of sphingomyelin, is required for the maintenance of plasma membrane microdomain fluidity, and has two isoforms: SMS1 and SMS2. Although these isoforms exhibit the same SMS activity, they are different enzymes with distinguishable subcellular localizations. It was reported that SMS2 KO mice displayed lower inflammatory responses and anti-atherosclerotic effects, suggesting that inhibition of SMS2 would be a potential therapeutic approach for controlling inflammatory responses and atherosclerosis.This study aimed to discover a novel small-molecule compound that selectively inhibits SMS2 enzymatic activity. We developed a human SMS2 enzyme assay with a high-throughput mass spectrometry-based screening system. We characterized the enzymatic properties of SMS2 and established a high throughput screening-compatible assay condition. To identify human SMS2 inhibitors, we conducted compound screening using the enzyme assay. We identified a 2-quinolone derivative as a SMS2 selective inhibitor with an IC50 of 950 nM and >100-fold selectivity for SMS2 over SMS1. The 2-quinolone exhibited efficacy in a cell-based engagement assay. We demonstrated that a more potent derivative directly bound to SMS2-expressing membrane fractions in an affinity selection mass spectrometry assay. Mutational analyses revealed that the interaction of the inhibitor with SMS2 required the presence of the amino acids 5227 and H229, which are located in the catalytic domain of SMS2.In conclusion, we discovered novel SMS2-selective inhibitors. 2-Quinolone SMS2 inhibitors are considered applicable for leading optimization studies. Further investigations using these SMS2 inhibitors would provide validation tools for SMS2-relevant pathways in vitro and in vivo. (C)2017 Elsevier Masson SAS. All rights reserved.
• Discovery of 1,8-naphthyridin-2-one derivative as a potent and selective sphingomyelin synthase 2 inhibitor
  作者：Takafumi Yukawa、Takashi Nakahata、Rei Okamoto、Yuji Ishichi、Yasufumi Miyamoto、Satoshi Nishimura、Tatsuo Oikawa、Kazuki Kubo、Ryutaro Adachi、Yoshinori Satomi、Masanori Nakakariya、Nobuyuki Amano、Masahiro Kamaura、Nobuyuki Matsunaga

  DOI：10.1016/j.bmc.2020.115376

  日期：2020.4

  solubility, adjustment of lipophilicity was attempted and 1,8-naphthyridin-2-one 37 was identified as a potent and selective SMS2 inhibitor. A significant reduction in hepatic sphingomyelin levels following repeated treatment in mice suggested that compound 37 could be an effective in vivo tool for clarifying the role of SMS2 enzyme and developing the treatment for SMS2-related diseases.

  鞘磷脂合酶2（SMS2）作为治疗各种心血管疾病和代谢疾病的药物靶标已引起关注。高通量筛选命中2-喹诺酮10的修饰在纳摩尔浓度下增强了对SMS2的抑制，对SMS1具有良好的选择性。为了改善诸如被动膜渗透性和水溶性的药物特性，尝试调节亲脂性，并且将1，8-萘啶-2-酮37鉴定为有效和选择性的SMS2抑制剂。在小鼠中反复治疗后，肝鞘磷脂水平显着降低，表明化合物37可能是一种有效的体内工具，用于阐明SMS2酶的作用并发展针对SMS2相关疾病的治疗方法。