ethyl 2-((4,6-dihydroxypyrimidin-2-yl)thio)hexanoate | 916482-23-0

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: ethyl 2-((4,6-dihydroxypyrimidin-2-yl)thio)hexanoate
• 英文别名: ethyl 2-[(4-hydroxy-6-oxo-1H-pyrimidin-2-yl)sulfanyl]hexanoate
• CAS: 916482-23-0
• 化学式: C₁₂H₁₈N₂O₄S
• 分子量: 286.352
• InChiKey: TXADGEWJMPGDON-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 2-((4,6-dihydroxypyrimidin-2-yl)thio)hexanoate 在 三氯氧磷 作用下， 生成 ethyl 2-((4,6-dichloropyrimidin-2-yl)thio)hexanoate
  参考文献：
  名称：

  α-烷基取代的哌立尼克酸衍生物作为过氧化物酶体增殖物激活受体α和γ的强效双重激动剂

  摘要：

  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。

  DOI：

  10.1002/ardp.200700209
• 作为产物：
  描述：

  2-溴己酸乙酯 、 2-Thiobarbituric acid 在 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 ethyl 2-((4,6-dihydroxypyrimidin-2-yl)thio)hexanoate
  参考文献：
  名称：

  改善PPARα活性的分子决定因素：吡ix酸衍生物的构效关系，PPARα的对接研究和定点诱变

  摘要：

  过氧化物酶体增殖物激活受体（PPARs）是治疗代谢综合征的有吸引力的靶标。特别是PPARα和PPARγ激动活性的组合似乎值得追求。本文中，我们提出了一系列具有有效PPARα特别是具有2-（（4-氯-6-（（（4-（苯基氨基）苯基）氨基）嘧啶-2-基）PPARα/γ双重激动剂作用的吡rin酸衍生物的设计和合成。 ）硫）辛酸具有最高的潜力。我们基于分子对接和结构-活性关系（SAR）研究的研究阐明了影响PPARα效能的结构决定因素。二苯胺支架似乎起着关键作用。仔细的计算机分析表明，二苯胺和水簇之间的氢键起着至关重要的作用。

  DOI：

  10.1016/j.bmcl.2014.05.058

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。
• Design, Synthesis, and Biological Evaluation of a Novel Class of γ-Secretase Modulators with PPARγ Activity
  作者：Martina Hieke、Julia Ness、Ramona Steri、Michaela Dittrich、Christine Greiner、Oliver Werz、Karlheinz Baumann、Manfred Schubert-Zsilavecz、Sascha Weggen、Heiko Zettl

  DOI：10.1021/jm1003073

  日期：2010.6.24

  We present a novel class of dual modulators of gamma-secretase and peroxisome proliferator-activated receptor gamma (PPAR gamma) based on the structure of 2-(bis(phenethoxy)pyrimidine-2-ylthio)hexanoic acid 8 (IC50(A beta 42) = 22.8 mu M, EC50(PPAR gamma) = 8.3 mu M). The modulation of both targets with approved drugs (i.e., amyloid-beta 42 (A beta 42)-lowering NSAIDs for gamma-secretase and glitazones for PPAR gamma) has demonstrated beneficial effects in in vitro and in vivo models of Alzheimer's disease (AD). However, although NSAIDs and PPAR gamma agonists share similar structural features, no druglike compounds with dual activities as gamma-secretase modulators (GSMs) and PPAR gamma agonists have been designed so far. On the basis of our initial lead structure 8, we present the structure-activity relationships (SARs) of broad structural variations. A significant improvement was reached by the introduction of p-trifluoromethyl substituents at the phenyl residues yielding compound 16 (IC50(A beta 42) = 6.0 mu M, EC50(PPAR gamma) = 11.0 mu M) and the replacement of the two phenyl residues of 8 by cyclohexyl yielding compound 22 (IC50(A beta 42) = 5.1 mu M, EC50(PPAR gamma) = 6.6 mu M).
• Pirinixic Acid Derivatives as Novel Dual Inhibitors of Microsomal Prostaglandin E₂ Synthase-1 and 5-Lipoxygenase
  作者：Andreas Koeberle、Heiko Zettl、Christine Greiner、Mario Wurglics、Manfred Schubert-Zsilavecz、Oliver Werz

  DOI：10.1021/jm801085s

  日期：2008.12.25

  Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2.3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly a substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2.3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC50 = 1.3 and 1 mu M, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacologial profile and a potential for therapeutic use.
• Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition
  作者：Thomas Hanke、Christina Lamers、Roberto Carrasco Gomez、Gisbert Schneider、Oliver Werz、Manfred Schubert-Zsilavecz

  DOI：10.1016/j.bmcl.2014.06.077

  日期：2014.8

  relationship of these aminothiazole-featured pirinixic acids as dual PPARα/γ agonists and discuss their advantages with their potential as dual 5-LO/mPGES-1 inhibitors in inflammatory and cancer diseases. Various pirinixic acid derivatives had already been identified as dual PPARα/γ agonists. However, within this series of aminothiazole-featured pirinixic acids we were able to identify the most potent

  最初提出双重PPARα/γ激活的概念作为治疗代谢综合征的新方法。但是，最近的结果表明，PPARα以及PPARγ活化也可能对炎症性疾病和癌症的治疗有益。我们最近已确定氨基噻唑为特征的吡rin酸为双5-脂氧合酶（5-LO）和微粒体前列腺素E 2合酶1（mPGES-1）抑制剂。在这里，我们介绍了这些氨基噻唑特征的吡rin酸作为双重PPARα/γ激动剂的结构与活性之间的关系，并讨论了它们作为双重5-LO / mPGES-1抑制剂在炎性和癌症疾病中的潜力的优势。多种吡喃酸衍生物已被确定为双重PPARα/γ激动剂。然而，在这一系列氨基噻唑特色的吡rin酸中，我们能够鉴定出最有效的选择性PPARγ激动性吡rin酸衍生物（化合物13，（2-[（4-氯-6-[4-（萘-2-基）-1，3-噻唑-2-基]氨基}嘧啶-2-基）硫烷基]辛酸））。因此，进行13在PPARγ上的对接以确定潜在的结合模式。
• Molecular determinants for improved activity at PPARα: Structure–activity relationship of pirinixic acid derivatives, docking study and site-directed mutagenesis of PPARα
  作者：Christina Lamers、Michaela Dittrich、Ramona Steri、Ewgenij Proschak、Manfred Schubert-Zsilavecz

  DOI：10.1016/j.bmcl.2014.05.058

  日期：2014.8

  proliferator-activated receptors (PPARs) are attractive targets for the treatment of the metabolic syndrome. Especially a combination of PPARα and PPARγ agonistic activity seems worthwhile to be pursued. Herein we present the design and synthesis of a series of pirinixic acid derivatives as potent PPARα particularly dual PPARα/γ agonists with 2-((4-chloro-6-((4-(phenylamino)phenyl)amino)pyrimidin-2-yl)thio)octanoicacid

  过氧化物酶体增殖物激活受体（PPARs）是治疗代谢综合征的有吸引力的靶标。特别是PPARα和PPARγ激动活性的组合似乎值得追求。本文中，我们提出了一系列具有有效PPARα特别是具有2-（（4-氯-6-（（（4-（苯基氨基）苯基）氨基）嘧啶-2-基）PPARα/γ双重激动剂作用的吡rin酸衍生物的设计和合成。 ）硫）辛酸具有最高的潜力。我们基于分子对接和结构-活性关系（SAR）研究的研究阐明了影响PPARα效能的结构决定因素。二苯胺支架似乎起着关键作用。仔细的计算机分析表明，二苯胺和水簇之间的氢键起着至关重要的作用。