Identification of new γ-hydroxybutenolides that preferentially inhibit the activity of mPGES-1

Bioorg Med Chem. 2012 Aug 15;20(16):5012-6. doi: 10.1016/j.bmc.2012.06.032. Epub 2012 Jun 23.

Abstract

Microsomal prostaglandin E(2) synthase-1 (mPGES-1) has been recognized as novel, promising drug target for anti-inflammatory and anticancer drugs. mPGES-1 catalyzes the synthesis of the inducible prostaglandin E(2) in response to pro-inflammatory stimuli, rendering this enzyme extremely interesting in drug discovery process owing to the drastic reduction of the severe side effects typical for traditional non-steroidal anti-inflammatory drugs. In the course of our investigations focused on this topic, we identified two interesting molecules bearing the γ-hydroxybutenolide scaffold which potently inhibit the activity of mPGES-1. Notably, the lead compound 2c that inhibited mPGES-1 with IC(50) = 0.9 μM, did not affect other related enzymes within the arachidonic acid cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / chemical synthesis
  • 4-Butyrolactone / chemistry
  • 4-Butyrolactone / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / metabolism
  • Molecular Structure
  • Prostaglandin-E Synthases
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • 4-Butyrolactone