2-[(4-chloro-6-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-2-(naphthalen-1-yl)acetic acid

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 2-[(4-chloro-6-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-2-(naphthalen-1-yl)acetic acid
• 英文别名: 2-[4-Chloro-6-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]pyrimidin-2-yl]sulfanyl-2-naphthalen-1-ylacetic acid；2-[4-chloro-6-[[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino]pyrimidin-2-yl]sulfanyl-2-naphthalen-1-ylacetic acid
• 化学式: C₂₅H₁₆Cl₂N₄O₂S₂
• 分子量: 539.466
• InChiKey: UCPBLSHCPJHPDF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.1
• 重原子数：
  35
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  142
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  ethyl 2-[(4-chloro-6-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-2-(naphthalen-1-yl)acetate 在 lithium hydroxide monohydrate 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 24.0h， 以43%的产率得到2-[(4-chloro-6-{[4-(4-chlorophenyl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]-2-(naphthalen-1-yl)acetic acid
  参考文献：
  名称：

  Aminothiazole-Featured Pirinixic Acid Derivatives As Dual 5-Lipoxygenase and Microsomal Prostaglandin E₂ Synthase-1 Inhibitors with Improved Potency and Efficiency in Vivo

  摘要：

  Dual inhibition of microsomal prostaglandin E-2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 mu M, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 mu M) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E-2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.

  DOI：

  10.1021/jm401557w

文献信息

• Aminothiazole-Featured Pirinixic Acid Derivatives As Dual 5-Lipoxygenase and Microsomal Prostaglandin E₂ Synthase-1 Inhibitors with Improved Potency and Efficiency in Vivo
  作者：Thomas Hanke、Friederike Dehm、Stefanie Liening、Sven-Desiderius Popella、Jonas Maczewsky、Max Pillong、Jens Kunze、Christina Weinigel、Dagmar Barz、Astrid Kaiser、Mario Wurglics、Michael Lämmerhofer、Gisbert Schneider、Lidia Sautebin、Manfred Schubert-Zsilavecz、Oliver Werz

  DOI：10.1021/jm401557w

  日期：2013.11.27

  Dual inhibition of microsomal prostaglandin E-2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) is currently pursued as potential pharmacological strategy for treatment of inflammation and cancer. Here we present a series of 26 novel 2-aminothiazole-featured pirinixic acid derivatives as dual 5-LO/mPGES-1 inhibitors with improved potency (exemplified by compound 16 (2-[(4-chloro-6-[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid) with IC50 = 0.3 and 0.4 mu M, respectively) and bioactivity in vivo. Computational analysis presumes binding sites of 16 at the tip of the 5-LO catalytic domain and within a subpocket of the mPGES-1 active site. Compound 16 (10 mu M) hardly suppressed cyclooxygenase (COX)-1/2 activities, failed to inhibit 12/15-LOs, and is devoid of radical scavenger properties. Finally, compound 16 reduced vascular permeability and inflammatory cell infiltration in a zymosan-induced mouse peritonitis model accompanied by impaired levels of cysteinyl-leukotrienes and prostaglandin E-2. Together, 2-aminothiazole-featured pirinixic acids represent potent dual 5-LO/mPGES-1 inhibitors with an attractive pharmacological profile as anti-inflammatory drugs.