Discovery and biological evaluation of a novel class of dual microsomal prostaglandin E2 synthase-1/5-lipoxygenase inhibitors based on 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid

J Med Chem. 2011 Jul 14;54(13):4490-507. doi: 10.1021/jm200092b. Epub 2011 Jun 8.

Abstract

Various inflammatory diseases are associated with the excessive formation of leukotrienes (LTs) and prostaglandins (PGs). Herein, we present a novel class of dual inhibitors of 5-lipoxygenase (5-LO) and microsomal prostaglandin E(2) synthase-1 (mPGES-1), key enzymes in the formation of LTs and PGE(2), respectively. On the basis of the structure of 2-[(4,6-diphenethoxypyrimidin-2-yl)thio]hexanoic acid (1), we performed a detailed SAR analysis, and mechanistic studies were carried out to elucidate the mode of 5-LO inhibition. Interestingly, the pyrimidine ring including the thioether of 1 could be replaced by a simple benzyl or a benzylidene moiety yielding a novel series of bioactive 2-benzylidene- and 2-benzylhexanoic acids exemplified by 2-(2,3-diphenethoxybenzylidene)hexanoic acid, 29 (IC(50) 5-LO = 0.8 μM; mPGES-1 = 1.1 μM). Importantly, none of the novel bioactive derivatives strongly inhibited cyclooxygenase activities. Together, we provide novel promising lead compounds for the treatment of inflammatory diseases valuable for further investigations in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Inflammatory Agents, Non-Steroidal / chemical synthesis*
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Arachidonate 5-Lipoxygenase / chemistry
  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / pharmacology
  • Binding Sites
  • Caproates / chemical synthesis*
  • Caproates / chemistry
  • Caproates / pharmacology
  • Cells, Cultured
  • Cyclooxygenase Inhibitors / chemical synthesis
  • Cyclooxygenase Inhibitors / chemistry
  • Cyclooxygenase Inhibitors / pharmacology
  • Humans
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Intramolecular Oxidoreductases / chemistry
  • Ligands
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology
  • Microsomes / enzymology*
  • Models, Molecular
  • Prostaglandin-E Synthases
  • Pyrimidines / chemical synthesis*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Recombinant Proteins / chemistry
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Benzene Derivatives
  • Caproates
  • Cyclooxygenase Inhibitors
  • Ligands
  • Lipoxygenase Inhibitors
  • Pyrimidines
  • Recombinant Proteins
  • Arachidonate 5-Lipoxygenase
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases