A novel class of dual mPGES-1/5-LO inhibitors based on the α-naphthyl pirinixic acid scaffold

Bioorg Med Chem Lett. 2011 Mar 1;21(5):1329-33. doi: 10.1016/j.bmcl.2011.01.049. Epub 2011 Jan 18.

Abstract

Dual inhibition of microsomal prostaglandin E(2) synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) represents a promising strategy in the development of novel anti-inflammatory drugs targeting the arachidonic acid cascade. Herein, a class of α-naphthyl pirinixic acids is characterized as dual mPGES-1/5-LO inhibitors. Systematic structural variation was focused on the lipophilic backbone of the scaffold and yielded detailed structure-activity relationships (SAR) with compound 16 (IC(50) mPGES-1=0.94 μM; IC(50) 5-LO=0.1 μM) showing the most favorable in vitro pharmacological profile.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents / chemical synthesis*
  • Anti-Inflammatory Agents / chemistry*
  • Anti-Inflammatory Agents / pharmacology
  • Arachidonate 5-Lipoxygenase / chemistry*
  • Inhibitory Concentration 50
  • Intramolecular Oxidoreductases / antagonists & inhibitors
  • Intramolecular Oxidoreductases / chemistry*
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry*
  • Lipoxygenase Inhibitors / pharmacology
  • Models, Biological
  • Molecular Structure
  • Naphthols / chemistry*
  • Prostaglandin-E Synthases
  • Pyrimidines / chemistry*
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents
  • Lipoxygenase Inhibitors
  • Naphthols
  • Pyrimidines
  • pirinixic acid
  • Arachidonate 5-Lipoxygenase
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases