Pharmacology of the pyrroloimidazole, SK&F 105809--I. Inhibition of inflammatory cytokine production and of 5-lipoxygenase- and cyclooxygenase-mediated metabolism of arachidonic acid.
SK&F 105809 [2-(4- methylsulfinylphenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2- a] imidazole] was determined to be a prodrug for the sulfide metabolite SK&F 105561 [2-(4- methylthiophenyl)-3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a] imidazole] which inhibited interleukin-1 (IL-1) production in vitro and both 5-lipoxygenase (5-LO) and prostaglandin H (PGH) synthase activities in vitro and ex vivo. SK&F 105561 inhibited partially purified 5-LO with a half-maximal concentration (IC50) of 3 microM. This inhibition was reversible, independent of preincubation time, and dependent on the concentration of the substrate arachidonic acid. SK&F 105561 also inhibited purified PGH synthase with the potency dependent on the level of peroxidase activity. The IC50 was 100 microM in the absence of peroxidase activity, whereas an IC50 of 3 microM was observed in the presence of peroxidase activity. Using human monocytes, SK&F 105561 inhibited A23187-stimulated prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) production with IC50 values of 0.1 and 2 microM, respectively. In addition, IL-1 production by lipopolysaccharide-stimulated human monocytes was also inhibited (IC50 2 microM). Oral administration of SK&F 105809 to rats resulted in a dose-related generation of SK&F 105561 and in the inhibition of thromboxane B2 and LTB4 production ex vivo with a half-maximal dose (ED50) of 15 and 60 mg/kg, respectively. SK&F 105561 showed weak inhibitory activity on 12-lipoxygenase with an IC50 of greater than 200 microM. Neither SK&F 105561 nor SK&F 105809 inhibited the stimulated-turnover of arachidonic acid-containing phospholipids in human monocytes or the activity of cell-free phospholipases A2 and C. Moreover, neither SK&F 105561 nor SK&F 105809 antagonized the binding of LTB4 or leukotriene D4 to membrane receptors. From these results, SK&F 105561, the active principle of SK&F 105809, acts as an inhibitor of both inflammatory cytokine and eicosanoid production.
Marshall
P J
PJ
Department of Respiratory/Inflammation Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Griswold
D E
DE
Breton
J
J
Webb
E F
EF
Hillegass
L M
LM
Sarau
H M
HM
Newton
J
J
Lee
J C
JC
Bender
P E
PE
Hanna
N
N
D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines / Q000096:biosynthesis*; D015777:Eicosanoids / Q000096:biosynthesis* / Q000097:blood; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007249:Inflammation / Q000378:metabolism; D007375:Interleukin-1 / Q000096:biosynthesis; D015289:Leukotrienes / Q000378:metabolism; D016859:Lipoxygenase Inhibitors; D008297:Male; D010740:Phospholipases / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011355:Prodrugs / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
D001095:Arachidonic Acids; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D015777:Eicosanoids; D007093:Imidazoles; D007375:Interleukin-1; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010743:Phospholipids; D011355:Prodrugs; C067915:SK&F 105561; C067914:SK&F 105809; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases; D010740:Phospholipases