N-[3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propyl]-6-(2,2,2-trifluoroethoxy)nicotinamide | 1190440-14-2

• 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: N-[3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propyl]-6-(2,2,2-trifluoroethoxy)nicotinamide
• 英文别名: N-[3-(4-Fluorophenyl)-3-(4-methanesulfonyl-phenyl)-propyl]-6-(2,2,2-trifluoro-ethoxy)-nicotinamide；N-[3-(4-fluorophenyl)-3-(4-methylsulfonylphenyl)propyl]-6-(2,2,2-trifluoroethoxy)pyridine-3-carboxamide
• CAS: 1190440-14-2
• 化学式: C₂₄H₂₂F₄N₂O₄S
• 分子量: 510.509
• InChiKey: PMLBVNNUFYWONH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  35
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  93.7
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  6(2,2,2-三氟乙氧基)吡啶-3-羧酸 、 3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propylamine 在 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 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以89%的产率得到N-[3-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)propyl]-6-(2,2,2-trifluoroethoxy)nicotinamide
  参考文献：
  名称：

  Structure-Based Optimization of Arylamides as Inhibitors of Soluble Epoxide Hydrolase

  摘要：

  Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of all effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection, The screen identified N-(3,3-diphenylpropyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.

  DOI：

  10.1021/jm9005302

文献信息

• Structure-Based Optimization of Arylamides as Inhibitors of Soluble Epoxide Hydrolase
  作者：Anne B. Eldrup、Fariba Soleymanzadeh、Steven J. Taylor、Ingo Muegge、Neil A. Farrow、David Joseph、Keith McKellop、Chuk C. Man、Alison Kukulka、Stéphane De Lombaert

  DOI：10.1021/jm9005302

  日期：2009.10.8

  Inhibition of soluble epoxide hydrolase (sEH) is hypothesized to lead to an increase in circulating levels of epoxyeicosatrienoic acids, resulting in the potentiation of their in vivo pharmacological properties. As part of all effort to identify inhibitors of sEH with high and sustained plasma exposure, we recently performed a high throughput screen of our compound collection, The screen identified N-(3,3-diphenylpropyl)-nicotinamide as a potent inhibitor of sEH. Further profiling of this lead revealed short metabolic half-lives in microsomes and rapid clearance in the rat. Consistent with these observations, the determination of the in vitro metabolic profile of N-(3,3-diphenyl-propyl)-nicotinamide in rat liver microsomes revealed extensive oxidative metabolism and a propensity for metabolite switching. Lead optimization, guided by the analysis of the solid-state costructure of N-(3,3-diphenyl-propyl)-nicotinamide bound to human sEH, led to the identification of a class of potent and selective inhibitors. An inhibitor from this class displayed an attractive in vitro metabolic profile and high and sustained plasma exposure in the rat after oral administration.