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SK&F 105809 {2-(4- methylsulfinylphenyl )-3-(4- pyridyl )-6,7- dihydro -[5H]- pyrrolo [l,2-a] imidazole} was determined to be a prodrug for the sulfide metabolite SK&F 105561 {2-(4- methyltniophenyl )-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 ( ic 50 ) of 3 μM. 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 ic 50 was 100 μM in the absence of peroxidase activity, whereas an ic 50 of 3 μM was observed in the presence of peroxidase activity. Using human monocytes, SK&F 105561 inhibited A23187-stimulated prostaglandin E 2 (PGE 2 ) and leukotriene B 4 (LTB 4 ) production with ic 50 values of 0.1 and 2 μM, respectively. In addition, IL-1 production by lipopolysaccharide-stimulated human monocytes was also inhibited ( ic 50 2 μM). Oral administration of SK&F 105809 to rats resulted in a dose-related generation of SK&F 105561 and in the inhibition of thromboxane B 2 and LTB 4 production ex vivo with a half-maximal dose ( ed 50 ) of 15 and 60 mg/kg, respectively. SK&F 105561 showed weak inhibitory activity on 12-lipoxygenase with an ic 50 of greater than 200 μM. 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 A 2 and C. Moreover, neither SK&F 105561 nor SK&F 105809 antagonized the binding of LTB 4 or leukotriene D 4 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. |
