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

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.