The anti-inflammatory effects of ZLJ-6, a novel dual cyclooxygenase/5-lipoxygenase inhibitor

Eur J Pharmacol. 2009 Apr 1;607(1-3):244-50. doi: 10.1016/j.ejphar.2009.02.032. Epub 2009 Feb 23.

Abstract

Compound ZLJ-6 [(Z)-1-methyl-1,5-dihydro-2-amino-5-[4-(mesyl)benzylidene]-4H-imi-dazole-4-one mesilate] is a potent inhibitor of cyclooxygenase (IC(50)=0.73 and 0.31 microM, for cyclooxygenase-1 and cyclooxygenase-2 respectively) in human whole blood. It also inhibited the production of thromboxane B(2) and prostaglandin E(2) in calcium ionophore A23187-induced human (IC(50)=0.50 microM) and rat whole blood (IC(50)=0.93 microM), and rat peritoneal leukocytes (IC(50)=2.27 microM). ZLJ-6 suppressed the activity of 5-lipoxygenase in the rat basophilic leukemia (RBL-1) cell lysate (IC(50)=0.32 microM) and in intact cells (IC(50)=1.06 microM) and reduced the generation of leukotriene B(4) (LTB(4)) in A23187-stimulated human (IC(50)=1.61 microM) or rat whole blood (IC(50)=0.99 microM), and rat peritoneal leukocytes (IC(50)=2.59 microM). In vivo, ZLJ-6, administered orally, demonstrated potent anti-inflammatory activity in the carrageenin-induced paw oedema model in rats and showed analgesic activity in the acetic acid-induced abdominal construction model in mice. No gastrointestinal ulcers were found with the anti-inflammatory dose (30 mg/kg) in normal rats. These results indicated that ZLJ-6 potently inhibited 5-lipoxygenase and cyclooxygenase, and blocked the production of LTB(4), TXB(2) and PGE(2). Thus ZLJ-6 is an ideal substitute for classical non-steroidal anti-inflammatory therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Inflammatory Agents / administration & dosage
  • Anti-Inflammatory Agents / pharmacology*
  • Anti-Inflammatory Agents / toxicity
  • Carrageenan
  • Cyclooxygenase 1 / drug effects
  • Cyclooxygenase 1 / metabolism
  • Cyclooxygenase 2 / drug effects
  • Cyclooxygenase 2 / metabolism
  • Cyclooxygenase Inhibitors / administration & dosage
  • Cyclooxygenase Inhibitors / pharmacology*
  • Cyclooxygenase Inhibitors / toxicity
  • Dinoprostone / antagonists & inhibitors
  • Disease Models, Animal
  • Edema / drug therapy*
  • Edema / physiopathology
  • Female
  • Humans
  • Imidazoles / administration & dosage
  • Imidazoles / pharmacology*
  • Imidazoles / toxicity
  • Inhibitory Concentration 50
  • Leukocytes / drug effects
  • Leukocytes / metabolism
  • Leukotriene B4 / antagonists & inhibitors
  • Lipoxygenase Inhibitors / administration & dosage
  • Lipoxygenase Inhibitors / pharmacology
  • Lipoxygenase Inhibitors / toxicity
  • Male
  • Rats
  • Rats, Sprague-Dawley
  • Sulfones / administration & dosage
  • Sulfones / pharmacology*
  • Sulfones / toxicity
  • Thromboxane B2 / antagonists & inhibitors

Substances

  • 1-methyl-1,5-dihydro-2-amino-5-(4-(mesyl)benzylidene)-4H-imidazole-4-one
  • Anti-Inflammatory Agents
  • Cyclooxygenase Inhibitors
  • Imidazoles
  • Lipoxygenase Inhibitors
  • Sulfones
  • Leukotriene B4
  • Thromboxane B2
  • Carrageenan
  • Cyclooxygenase 1
  • Cyclooxygenase 2
  • Dinoprostone