Structure-based discovery of inhibitors of microsomal prostaglandin E2 synthase-1, 5-lipoxygenase and 5-lipoxygenase-activating protein: promising hits for the development of new anti-inflammatory agents

J Med Chem. 2011 Mar 24;54(6):1565-75. doi: 10.1021/jm101238d. Epub 2011 Feb 16.

Abstract

Microsomal prostaglandin E(2) synthase (mPGES)-1 catalyzes the transformation of PGH(2) to PGE(2) that is involved in several pathologies like fever, pain, and inflammatory disorders. To identify novel mPGES-1 inhibitors, we used in silico screening to rapidly direct the synthesis, based on the copper-catalyzed 3 + 2 Huisgen's reaction (click chemistry), of potential inhibitors. We designed 26 new triazole-based compounds in accordance with the pocket binding requirements of human mPGES-1. Docking results, in agreement with ligand efficiency values, suggested the synthesis of 15 compounds that at least in theory were shown to be more efficient in inhibiting mPGES-1. Biological evaluation of these selected compounds has disclosed three new potential anti-inflammatory drugs: (I) compound 4 displaying selectivity for mPGES-1 with an IC(50) value of 3.2 μM, (II) compound 20 that dually inhibits 5-lipoxygenase and mPGES-1, and (III) compound 7 apparently acting as 5-lipoxygenase-activating protein inhibitor (IC(50) = 0.4 μM).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Lipoxygenase-Activating Protein Inhibitors / chemical synthesis*
  • 5-Lipoxygenase-Activating Protein Inhibitors / chemistry
  • 5-Lipoxygenase-Activating Protein Inhibitors / pharmacology
  • 5-Lipoxygenase-Activating Proteins / chemistry*
  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry
  • Anti-Inflammatory Agents / pharmacology
  • Arachidonate 5-Lipoxygenase / chemistry*
  • Catalytic Domain
  • Cell Line, Tumor
  • Humans
  • In Vitro Techniques
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / chemistry
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology
  • Microsomes / enzymology
  • Models, Molecular*
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Prostaglandin-E Synthases
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • 5-Lipoxygenase-Activating Protein Inhibitors
  • 5-Lipoxygenase-Activating Proteins
  • Anti-Inflammatory Agents
  • Lipoxygenase Inhibitors
  • Triazoles
  • Arachidonate 5-Lipoxygenase
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases