ethyl 2-[(4,6-dichloropyrimidin-2-yl)sulfanyl]-2-(naphthalene-1-yl)acetate | 916482-31-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: ethyl 2-[(4,6-dichloropyrimidin-2-yl)sulfanyl]-2-(naphthalene-1-yl)acetate
• CAS: 916482-31-0
• 化学式: C₁₈H₁₄Cl₂N₂O₂S
• 分子量: 393.293
• InChiKey: NDTNVJAMZFXHCO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.33
• 重原子数：
  25.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  52.08
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  ethyl 2-[(4,6-dichloropyrimidin-2-yl)sulfanyl]-2-(naphthalene-1-yl)acetate 在 三乙胺 、 potassium hydroxide 作用下， 以 乙醇 为溶剂， 生成 2-(4-chloro-6-(2,3-dihydro-1H-inden-5-ylamino)pyrimidin-2-ylthio)-2-(naphthalen-1-yl)acetic acid
  参考文献：
  名称：

  A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold

  摘要：

  Dual inhibition of microsomal prostaglandin E-2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of alpha-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC50 mPGES-1 = 0.94 mu M; IC50 5-LO = 0.1 mu M) showing the most favorable in vitro pharmacological profile. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.01.049
• 作为产物：
  描述：

  Alpha-溴代-1-萘乙酸乙酯 在 三乙胺 、 N,N-二乙基苯胺 、 三氯氧磷 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 生成 ethyl 2-[(4,6-dichloropyrimidin-2-yl)sulfanyl]-2-(naphthalene-1-yl)acetate
  参考文献：
  名称：

  A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold

  摘要：

  Dual inhibition of microsomal prostaglandin E-2 synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of alpha-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC50 mPGES-1 = 0.94 mu M; IC50 5-LO = 0.1 mu M) showing the most favorable in vitro pharmacological profile. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.01.049

文献信息

• α-Alkyl Substituted Pirinixic Acid Derivatives as Potent Dual Agonists of the Peroxisome Proliferator Activated Receptor Alpha and Gamma
  作者：Oliver Rau、Yvonne Syha、Heiko Zettl、Michael Kock、Andreas Bock、Manfred Schubert-Zsilavecz

  DOI：10.1002/ardp.200700209

  日期：2008.3

  Peroxisome proliferator‐activated receptors (PPAR) are nuclear receptors, playing a pivotal role in energy homeostasis. Activators of the PPARα subtype are in widespread use for the treatment of hyperlipidemia, while activators of the PPARγ subtype are in clinical use for the treatment of type‐2 diabetes. Since both of these diseases are frequently associated, the combined treatment with one drug simultaneously

  过氧化物酶体增殖物激活受体 (PPAR) 是核受体，在能量稳态中起关键作用。PPARα 亚型激活剂广泛用于治疗高脂血症，而 PPARγ 亚型激活剂在临床上用于治疗 2 型糖尿病。由于这两种疾病经常相互关联，因此用一种同时激活 PPARα 和 PPARγ 的药物进行联合治疗似乎是值得的。从吡立昔酸开始，它是一种中等活性的双 PPARα/γ 激动剂，我们通过用脂肪链取代 α- 位来提高对人 PPARα 和 PPARγ 的效力。分别在四个碳和六个碳的链长处达到最大效果，导致 PPARα 的活性诱导因子分别为 36 和 PPARγ 的因子为 18。
• 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.
• Rational design of a pirinixic acid derivative that acts as subtype-selective PPARγ modulator
  作者：Theresa M. Thieme、Ramona Steri、Ewgenij Proschak、Alexander Paulke、Gisbert Schneider、Manfred Schubert-Zsilavecz

  DOI：10.1016/j.bmcl.2010.03.008

  日期：2010.4

  Peroxisome proliferator-activated receptor gamma (PPAR gamma) is involved in glucose and lipid homeostasis. PPAR gamma agonists are in clinical use for the treatment of type 2 diabetes. Lately, a new class of selective PPAR gamma modulators (SPPAR gamma Ms) was developed, which are believed to show less side effects than full PPAR gamma agonists. We have previously shown that alpha-substitution of pirinixic acid, a moderate agonist of PPAR alpha and PPAR gamma, leads to low micromolar active balanced dual agonists of PPAR alpha and PPAR alpha. Herein we present modifications of pirinixic acid leading to subtype-selective PPAR gamma agonists and furthermore the development of a selective PPAR gamma modulator guided by molecular docking studies. (C) 2010 Elsevier Ltd. All rights reserved.