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.
Li
Liwen
L
Department of Pharmacology, China Pharmaceutical University, Nanjing 210009, PR China.
Ji
Hui
H
Sheng
Liang
L
Zhang
Yihua
Y
Lai
Yisheng
Y
Chen
Xiaorong
X
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002351:Carrageenan; D051545:Cyclooxygenase 1 / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D015232:Dinoprostone / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D020128:Inhibitory Concentration 50; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000633:toxicity; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013929:Thromboxane B2 / Q000037:antagonists & inhibitors
C541786:1-methyl-1,5-dihydro-2-amino-5-(4-(mesyl)benzylidene)-4H-imidazole-4-one; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D013450:Sulfones; D007975:Leukotriene B4; D013929:Thromboxane B2; D002351:Carrageenan; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone