Identification of pirinixic acid derivatives bearing a 2-aminothiazole moiety combines dual PPARα/γ activation and dual 5-LO/mPGES-1 inhibition

Bioorg Med Chem Lett. 2014 Aug 15;24(16):3757-63. doi: 10.1016/j.bmcl.2014.06.077. Epub 2014 Jul 3.


The concept of dual PPARα/γ activation was originally proposed as a new approach for the treatment of the metabolic syndrome. However, recent results indicated that PPARα as well as PPARγ activation might also be beneficial in the treatment of inflammatory diseases and cancer. We have recently identified aminothiazole-featured pirinixic acids as dual 5-lipoxygenase (5-LO) and microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitors. Here we present the structure-activity 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 selective PPARγ agonistic pirinixic acid derivative (compound 13, (2-[(4-chloro-6-{[4-(naphthalen-2-yl)-1,3-thiazol-2-yl]amino}pyrimidin-2-yl)sulfanyl]octanoic acid)). Therefore, docking of 13 on PPARγ was performed to determine the potential binding mode.

Keywords: 5-LO; Cancer; Inflammation; PPARα; PPARγ; mPGES-1.

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism*
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism
  • Models, Molecular
  • Molecular Structure
  • PPAR alpha / antagonists & inhibitors*
  • PPAR alpha / metabolism
  • PPAR gamma / antagonists & inhibitors*
  • PPAR gamma / metabolism
  • Prostaglandin-E Synthases
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology*
  • Structure-Activity Relationship
  • Thiazoles / chemistry


  • Enzyme Inhibitors
  • PPAR alpha
  • PPAR gamma
  • Pyrimidines
  • Thiazoles
  • 2-aminothiazole
  • pirinixic acid
  • Arachidonate 5-Lipoxygenase
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases