N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-(naphthalen-1-yl)-2-phenylethyl)piperidine-4-carboxamide | 1581755-29-4

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-(naphthalen-1-yl)-2-phenylethyl)piperidine-4-carboxamide
• 英文别名: N-(1,3-benzodioxol-5-ylmethyl)-1-(1-naphthalen-1-yl-2-phenylethyl)piperidine-4-carboxamide
• CAS: 1581755-29-4
• 化学式: C₃₂H₃₂N₂O₃
• 分子量: 492.618
• InChiKey: RPAVYYVXAHKRBX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.1
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  50.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  氰基萘 在 吡啶 、 盐酸 、 3-氯苯甲酰乙腈 、 sodium cyanide 、 palladium 10% on activated carbon 、 氢气 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 20.0~145.0 ℃ 、275.8 kPa 条件下， 反应 83.0h， 生成 N-(benzo[d][1,3]dioxol-5-ylmethyl)-1-(1-(naphthalen-1-yl)-2-phenylethyl)piperidine-4-carboxamide
  参考文献：
  名称：

  X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases

  摘要：

  Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.

  DOI：

  10.1021/jm401712t

文献信息

• X-ray Structural and Biological Evaluation of a Series of Potent and Highly Selective Inhibitors of Human Coronavirus Papain-like Proteases
  作者：Yahira M. Báez-Santos、Scott J. Barraza、Michael W. Wilson、Michael P. Agius、Anna M. Mielech、Nicole M. Davis、Susan C. Baker、Scott D. Larsen、Andrew D. Mesecar

  DOI：10.1021/jm401712t

  日期：2014.3.27

  Structure-guided design was used to generate a series of noncovalent inhibitors with nanomolar potency against the papain-like protease (PLpro) from the SARS coronavirus (CoV). A number of inhibitors exhibit antiviral activity against SARS-CoV infected Vero E6 cells and broadened specificity toward the homologous PLP2 enzyme from the human coronavirus NL63. Selectivity and cytotoxicity studies established a more than 100-fold preference for the coronaviral enzyme over homologous human deubiquitinating enzymes (DUBs), and no significant cytotoxicity in Vero E6 and HEK293 cell lines is observed. X-ray structural analyses of inhibitor-bound crystal structures revealed subtle differences between binding modes of the initial benzodioxolane lead (15g) and the most potent analogues 3k and 3j, featuring a monofluoro substitution at para and meta positions of the benzyl ring, respectively. Finally, the less lipophilic bis(amide) 3e and methoxypyridine 5c exhibit significantly improved metabolic stability and are viable candidates for advancing to in vivo studies.