Pirinixic acid derivatives as novel dual inhibitors of microsomal prostaglandin E2 synthase-1 and 5-lipoxygenase

J Med Chem. 2008 Dec 25;51(24):8068-76. doi: 10.1021/jm801085s.

Abstract

Dual inhibition of the prostaglandin (PG) and leukotriene (LT) biosynthetic pathway is supposed to be superior over single interference, both in terms of efficacy and side effects. Here, we present a novel class of dual microsomal PGE(2) synthase-1/5-lipoxygenase (5-LO) inhibitors based on the structure of pirinixic acid [PA, 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)acetic acid, compound 1]. Target-oriented structural modification of 1, particularly alpha substitution with extended n-alkyl or bulky aryl substituents and concomitant replacement of the 2,3-dimethylaniline by a biphenyl-4-yl-methane-amino residue, resulted in potent suppression of mPGES-1 and 5-LO activity, exemplified by 2-(4-(biphenyl-4-ylmethylamino)-6-chloropyrimidin-2-ylthio)octanoic acid (7b, IC(50) = 1.3 and 1 microM, respectively). Select compounds also potently reduced PGE(2) and 5-LO product formation in intact cells. Importantly, inhibition of cyclooxygenases-1/2 was significantly less pronounced. Taken together, these pirinixic acid derivatives constitute a novel class of dual mPGES-1/5-LO inhibitors with a promising pharmacological profile and a potential for therapeutic use.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Survival
  • Chemistry, Pharmaceutical / methods*
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / metabolism
  • Drug Design
  • Enzyme Activation
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry*
  • Humans
  • Inflammation
  • Inhibitory Concentration 50
  • Intramolecular Oxidoreductases / antagonists & inhibitors*
  • Lipoxygenase Inhibitors*
  • Models, Chemical
  • Prostaglandin-E Synthases
  • Pyrimidines / chemical synthesis
  • Pyrimidines / chemistry*

Substances

  • Enzyme Inhibitors
  • Lipoxygenase Inhibitors
  • Pyrimidines
  • pirinixic acid
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases