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

• Published in: European journal of pharmacology 2009-04, Vol.607 (1), p.244-250
• Main Authors: Li, Liwen, Ji, Hui, Sheng, Liang, Zhang, Yihua, Lai, Yisheng, Chen, Xiaorong
• Format: Article
• Language: English
• Subjects: Administration, Oral; Analgesics; Animals; Anti-Inflammatory Agents - administration & dosage; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - toxicity; Anti-inflammatory effect; Antiinflammatory agents; Arachidonate 5-lipoxygenase; Arachidonic acid; Basophilic leukemia; Biological and medical sciences; Blood; calcium ionophores; 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; Cyclooxygenase-1; Cyclooxygenase-2; Cyclooxygenase–lipoxygenase inhibitor; Dinoprostone - antagonists & inhibitors; Disease Models, Animal; Edema; Edema - drug therapy; Edema - physiopathology; Female; Gastrointestinal injury; Humans; Imidazoles - administration & dosage; Imidazoles - pharmacology; Imidazoles - toxicity; Inflammation; Inhibitory Concentration 50; Leukocytes - drug effects; Leukocytes - metabolism; Leukotriene B4; Leukotriene B4 - antagonists & inhibitors; Lipoxygenase Inhibitors - administration & dosage; Lipoxygenase Inhibitors - pharmacology; Lipoxygenase Inhibitors - toxicity; Male; Medical sciences; Peritoneum; Pharmacology. Drug treatments; Prostaglandin E2; Rats; Rats, Sprague-Dawley; Sulfones - administration & dosage; Sulfones - pharmacology; Sulfones - toxicity; Thromboxane B2 - antagonists & inhibitors; Thromboxanes; Ulcers
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2009.02.032

Compound ZLJ-6 [(Z)-1-methyl-1,5-dihydro-2-amino-5-[4-(mesyl)benzylidene]-4 H-imi-dazole-4-one mesilate] is a potent inhibitor of cyclooxygenase (IC 50 = 0.73 and 0.31 μM, 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 μM) and rat whole blood (IC 50 = 0.93 μM), and rat peritoneal leukocytes (IC 50 = 2.27 μM). ZLJ-6 suppressed the activity of 5-lipoxygenase in the rat basophilic leukemia (RBL-1) cell lysate (IC 50 = 0.32 μM) and in intact cells (IC 50 = 1.06 μM) and reduced the generation of leukotriene B 4 (LTB 4) in A23187-stimulated human (IC 50 = 1.61 μM) or rat whole blood (IC 50 = 0.99 μM), and rat peritoneal leukocytes (IC 50 = 2.59 μM). 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.