Molecular pharmacological profile of the nonredox-type 5-lipoxygenase inhibitor CJ-13,610

Br J Pharmacol. 2004 Jul;142(5):861-8. doi: 10.1038/sj.bjp.0705860. Epub 2004 Jun 14.

Abstract

5-Lipoxygenase (5-LO) is a crucial enzyme in the synthesis of the bioactive leukotrienes (LTs) from arachidonic acid (AA), and inhibitors of 5-LO are thought to prevent the untowarded pathophysiological effects of LTs. In this study, we present the molecular pharmacological profile of the novel nonredox-type 5-LO inhibitor CJ-13,610 that was evaluated in various in vitro assays. In intact human polymorphonuclear leukocytes (PMNL), challenged with the Ca(2+)-ionophore A23187, CJ-13,610 potently suppressed 5-LO product formation with an IC(50)=0.07 microm. Supplementation of exogenous AA impaired the efficacy of CJ-13,610, implying a competitive mode of action. In analogy to ZM230487 and L-739.010, two closely related nonredox-type 5-LO inhibitors, CJ-13,610 up to 30 microm failed to inhibit 5-LO in cell-free assay systems under nonreducing conditions, but inclusion of peroxidase activity restored the efficacy of CJ-13,610 (IC(50)=0.3 microm). In contrast to ZM230487 and L-739.010, the potency of CJ-13,610 does not depend on the cell stimulus or the activation pathway of 5-LO. Thus, 5-LO product formation in PMNL induced by phosphorylation events was equally suppressed by CJ-13,610 as compared to Ca(2+)-mediated 5-LO activation. In transfected HeLa cells, CJ-13,610 only slightly discriminated between phosphorylatable wild-type 5-LO and a 5-LO mutant that lacks phosphorylation sites. In summary, CJ-13,610 may possess considerable potential as a potent orally active nonredox-type 5-LO inhibitor that lacks certain disadvantages of former representatives of this class of 5-LO inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arachidonate 5-Lipoxygenase / metabolism*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cell-Free System
  • Cells, Cultured
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Glutathione Peroxidase / metabolism
  • HeLa Cells
  • Humans
  • Imidazoles / pharmacology*
  • Lipid Peroxides / metabolism
  • Lipoxygenase Inhibitors / pharmacology*
  • Neutrophils / drug effects
  • Neutrophils / enzymology
  • Oxidation-Reduction
  • Plasmids / genetics
  • Subcellular Fractions / drug effects
  • Subcellular Fractions / enzymology
  • Sulfides / pharmacology*
  • Transfection

Substances

  • CJ 13610
  • Imidazoles
  • Lipid Peroxides
  • Lipoxygenase Inhibitors
  • Sulfides
  • Glutathione Peroxidase
  • Arachidonate 5-Lipoxygenase