SK&F 86002: a structurally novel anti-inflammatory agent that inhibits lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid.
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 H2 (PGH2) synthase activity (IC50 120 microM) as well as prostanoid production by rat basophilic leukemia (RBL-1) cells (IC50 70 microM) and its sonicate (IC50 100 microM) and human monocytes (IC50 1 microM). 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 (IC50 10 microM). Cellular production of 5-lipoxygenase products was inhibited by SK&F 86002 as measured by leukotriene B4 (LTB4) generation from human neutrophils (IC50 20 microM), leukotriene C4 (LTC4) generation by human monocytes (IC50 20 microM), and 5-HETE production by RBL-1 cells (IC50 40 microM). 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.
Griswold
D E
DE
Smith Kline & French Laboratories, Philadelphia, PA 19101.
Marshall
P J
PJ
Webb
E F
EF
Godfrey
R
R
Newton
J
J
DiMartino
M J
MJ
Sarau
H M
HM
Gleason
J G
JG
Poste
G
G
Hanna
N
N
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001091:Arachidonate Lipoxygenases / Q000037:antagonists & inhibitors*; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D051379:Mice; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D013189:SRS-A / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D007093:Imidazoles; D016859:Lipoxygenase Inhibitors; D011720:Pyrazoles; D013189:SRS-A; D013844:Thiazoles; D007975:Leukotriene B4; D016718:Arachidonic Acid; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole; D001091:Arachidonate Lipoxygenases; C015429:phenidone