2-(4,6-diphenethoxypyrimidin-2-ylthio)acetic acid | 1077626-45-9

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 2-(4,6-diphenethoxypyrimidin-2-ylthio)acetic acid
• 英文别名: 2-[4,6-bis(2-phenylethoxy)pyrimidin-2-yl]sulfanylacetic acid
• CAS: 1077626-45-9
• 化学式: C₂₂H₂₂N₂O₄S
• 分子量: 410.494
• InChiKey: DQEBGENLFNMXNZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ethyl 2-(4,6-diphenethoxypyrimidin-2-ylthio)acetate 在 lithium hydroxide 作用下， 以 乙醇 为溶剂， 反应 24.0h， 生成 2-(4,6-diphenethoxypyrimidin-2-ylthio)acetic acid
  参考文献：
  名称：

  Pirinixic Acid Derivatives as Novel Dual Inhibitors of Microsomal Prostaglandin E₂ Synthase-1 and 5-Lipoxygenase

  摘要：

  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.

  DOI：

  10.1021/jm801085s

文献信息

• 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.
• [DE] PIRINIXINSÄURE-DERIVATE ALS PROSTAGLANDIN E2 SYNTHESE INHIBITOREN ZUR BEHANDLUNG VON ENTZÜNDLICHEN ERKRANKUNGEN<br/>[EN] PIRINIXIC ACID DERIVATIVES AS PROSTGLANDIN E2 SYNTHESIS INHIBITORS FOR TREATING INFLAMMATORY DISEASES<br/>[FR] DÉRIVÉS DE L'ACIDE PIRINIXIQUE COMME INHIBITEURS DE LA SYNTHÈSE DE LA PROSTAGLANDINE E2 POUR LE TRAITEMENT DE MALADIES INFLAMMATOIRES
  申请人：MEDEON PHARMACEUTICALS GMBH

  公开号：WO2009117985A1

  公开（公告）日：2009-10-01

  Die vorliegende Erfindung betrifft Pirinixinsäurederivate, insbesondere α-substituierten Pirinixinsäuren und Pirinixinsäureestem sowie deren strukturelle Derivaten mit der Strukturformel. Die Pirinixinsäurederivate hemmen die PGE2 Synthese, insbesondere die der mPGES-1. Ferner betrifft die Erfindung die Verwendung von diesen Pirinixinsäurederivaten zur Herstellung eines Arzneimittels zur Behandlung von Prostaglandin E2-vermittelten Erkrankungen, insbesondere von entzündlichen Erkrankungen, schmerzhaften und fiebrigen Zuständen, kardiovaskulären Ereignissen und Krebserkrankungen, die mit einer erhöhten Aktivität der induzierbaren mikrosomalen Prostaglandin E2 Synthase-1 (mPGES-1) bzw. erhöhten Prostaglandin E2 Synthese einhergehen.
• 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).