Inhibition of leukotriene biosynthesis and polymorphonuclear leukocyte functions by orally active quinolylmethoxyphenylamines.
The N-substituted quinolylmethoxyphenylamines, ETH603, ETH615 and ETH647, inhibited the formation of LTB4 in rat peritoneal leukocytes, human peripheral polymorphonuclear leukocytes and canine whole blood. In rat and human cells, the compounds also inhibited the formation of 5-HETE and stimulated the synthesis of 15-HETE. In rat leukocytes, the compounds were 15-30 times more potent inhibitors of LTB4 synthesis than nordihydroguaiaretic acid, but in canine whole blood they were significantly less potent, possibly due to protein binding. However, after oral administration of the compounds to dogs a long-lasting inhibition of LTB4 production in peripheral blood was observed at serum concentrations much lower than those required in vitro. Furthermore, the compounds inhibited the LTB4-directed chemotaxis and the phagocytosis of C. albicans blastospores by canine polymorphonuclear leukocytes both in vitro and following oral administration. The calcium ionophore A23187-induced release of LTB4 in the peritoneal cavity of rats was also inhibited by systemic administration of the compounds. We therefore conclude that these novel quinolines are orally active 5-lipoxygenase inhibitors which may accumulate in inflammatory cells in vivo, leading to potent inhibition of leukotriene biosynthesis and cell function.
Kirstein
D
D
Department of Pharmacology, Leo Pharmaceutical Products, Ballerup, Denmark.
Thomsen
M K
MK
Ahnfelt-Rønne
I
I
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D004285:Dogs; D005609:Free Radicals; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D066298:In Vitro Techniques; D017999:Leukotriene E4; D009504:Neutrophils / Q000187:drug effects*; D010587:Phagocytosis / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D013189:SRS-A / Q000031:analogs & derivatives* / Q000096:biosynthesis*
D001095:Arachidonic Acids; D005609:Free Radicals; D006893:Hydroxyeicosatetraenoic Acids; D011804:Quinolines; D013189:SRS-A; C069966:ETH 603; C069967:ETH 615; D016718:Arachidonic Acid; D000001:Calcimycin; C022022:5-hydroxy-6,8,11,14-eicosatetraenoic acid; D017999:Leukotriene E4