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

Griswold, Don E.; Marshall, Paul; Webb, Edward F.; Godfrey, Richard W.; Newton, John F.; DiMartino, Michael J.; Sarau, Henry M.; Gleason, John G.; Poste, George; Hanna, Nabil

doi:10.1016/0006-2952(87)90327-3

Cited by 72 publications

(48 citation statements)

References 27 publications

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“…A bicyclic imidazole, SK&F 86002, is a member of a class of compounds that has been demonstrated to specifically inhibit p38 MAPk activity with negligible effect on other MAP kinase members, MEK1, or c-Raf (34)(35)(36). Immunoprecipitated p38 MAPk from PAF or FMLP activated neutrophils was inhibited in a concentration dependent manner by SK&F 86002 with a greater then 95% decrease in activity at the highest level of inhibitor studied (Fig.…”

Section: Effect Of P38 Mapk Inhibition On Neutrophil Responses After mentioning

confidence: 99%

Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.

Nick

Avdi²,

Young³

et al. 1997

J. Clin. Invest.

292

256

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Section: Effect Of P38 Mapk Inhibition On Neutrophil Responses After mentioning

confidence: 99%

Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.

Nick

Avdi²,

Young³

et al. 1997

J. Clin. Invest.

292

256

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“…Previous studies had demonstrated that SK&F 86002 inhibited LTC4 and PGE 2 production by macrophages in vitro [3]. In order to examine a possible relationship between the oxygenase inhibitory activity of SK&F 86002 and its ability to inhibit IL-I production, we have tested a number of standard cyclooxygenase and/or lipoxygenase inhibitors for the inhibition of IL-I production.…”

Section: Resultsmentioning

confidence: 99%

“…Many of the activities, such as the stimulation of prostaglandin or collagenase production by synovial cells, activation of phospholipase C in chondrocytes, induction of proinflammatory molecules such as tumor necrosis factor and IL-6, have been implicated in disease processes. SK&F 86002 is a member of a novel class of antiinflammatory compounds, the dihydroimidazo thiazolines [3]. Aside from its anti-inflammatory activity evidenced in several animal models [4], we also demonstrated that the compound also had potent in vitro inhibitory effects on IL-I production [5].…”

Section: Introductionmentioning

confidence: 93%

Inhibitory effect of SK&F 86002 on monocyte IL-1 production

Lee¹,

Votta²,

Griswold³

et al. 1989

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The effects of several anti-inflammatory and anti-arthritic drugs on the in vitro production of interleukin-1 by human monocytes were examined. SK&F 86002-A2 was shown to be a potent inhibitor of IL-1 production with a 50% inhibitory concentration (IC50) of 1.3 +/- 0.5 microM. Standard compounds which inhibit the cyclooxygenase (CO) or CO and 5-lipoxygenase (5LO) pathways of arachidonic acid metabolism did not inhibit IL-1 production at nontoxic concentrations. Analysis of SK&F 86002 analogs also showed no clear correlation between 5LO and IL-1 synthesis inhibitory activity. The precise mechanism of action is not known except that it is post-transcriptional. Thus, SK&F 86002 may serve as a useful reagent in the understanding of the synthetic, processing and/or secretory pathways of interleukin-1, and may provide important insight into the treatment of disease states where aberrant IL-1 production is implicated.

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“…Like IL-I, TNF is produced by inflammatory macrophages and therefore, the inhibition of TNF production by SK&F 86002 may enhance its already impressive anti-inflammatory activity profile [8]. That SK&F 86002 exerts differential effects on the synthesis of these important cytokines provides a rationale for the development of selective inhibitors which regulate the expression of specific cytokines with potent pathophysiological effects.…”

Section: Tissue Culturementioning

confidence: 98%

Effect of SK&F 86002 on cytokine production by human monocytes

Lee¹,

Rebar²,

Laydon³

1989

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Human monocytes respond to a variety of stimuli in vitro by producing a number of physiologically important macromolecules including the cytokines. SK&F 86002, a dual inhibitor of the arachidonate metabolism, has been shown to inhibit LPS induced IL-1 production in human monocytes. We examined its effect on the production of other cytokines which are coordinately expressed as a result of LPS stimulation such as tumor necrosis factor alpha (TNF), alpha interferon (IFN-A), interferon beta-2 (IL-6) and granulocyte colony stimulating factor (g-CSF). The IC50 of SK&F 86002 for the TNF production was 5-8 microM, and greater than 20 microM for the other three cytokines. These IC50s were significantly higher than that previously reported for IL-1 production (1-2 microM). Taken together these data indicate that the inhibitory effect of SK&F 86002 on IL-1 production is selective and the production of cytokines in drug treated monocytes can be differentially affected.

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

Cited by 72 publications

References 27 publications

Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.

Common and distinct intracellular signaling pathways in human neutrophils utilized by platelet activating factor and FMLP.

Inhibitory effect of SK&F 86002 on monocyte IL-1 production

Effect of SK&F 86002 on cytokine production by human monocytes

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