SK&F 86002: A structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid

Abstract

The effects of SK&F 86002 [5-(4-pyridyl)-6 (4-fluorophenyl)-2,3-dihydroimidazo (2,1-b) thiazole] on the generation of eicosanoids in vitro and on inflammatory responses in vivo are described and compared to other non-steroidal anti-inflammatory drugs. SK&F 86002 inhibited prostaglandin H 2 (PGH 2) synthase activity ( ic 50 120 μM) as well as prostanoid production by rat basophilic leukemia (RBL-1) cells ( ic 50 70 μM) and its sonicate ( ic 50 100 μM) and human monocytes ( ic 50 1μM). In addition, SK&F 86002 inhibited the generation of dihydroxyeicosatetraenoic acid (diHETE) and 5-hydroxyeicosatetraenoic acid (5-HETE) by a high speed supernatant fraction of RBL-1 cells ( ic 50 10 μM). Cellular production of 5-lipoxygenase products was inhibited by SK&F 86002 as measured by leukotriene B 4 (LTB 4) generation from human neutrophils ( ic 50 20 μM), leukotriene C 4 (LTC 4) generation by human monocytes ( ic 50 20 μM), and 5-HETE production by RBL-1 cells ( ic 50 40 μM). The in vivo profile of anti-inflammatory activity of SK&F 86002 supports the dual inhibition of arachidonate metabolism as indicated by its activity in inflammation models that are insensitive to selective cyclooxygenase inhibitors. The responses of arachidonic-acid-induced edema in the mouse ear and rat paw, as well as the cell infiltration induced by carrageenan in the mouse peritoneum and by arachidonic acid in the rat air pouch, were inhibited by SK&F 86002 and phenidone but not by the selective cyclooxygenase inhibitors naproxen and indomethacin.