PYRIDINYL IMIDAZOLES INHIBIT THE INFLAMMATORY PHASE OF DELAYED-TYPE HYPERSENSITIVITY REACTIONS WITHOUT AFFECTING T-DEPENDENT IMMUNE-RESPONSES

The effects of pyridinyl imidazoles, specifically SK&F 105809 and its metabolite, on normal T-cell and B-cell mediated immune responses were examined and compared to the fungal macrolide immunosuppressives, cyc losporin A, FK506 and rapamycin and to the corticosteroid, dexamethaso ne. The orally active prodrug SK&F 105809 nyl)-3-(4-pyridyl)-6,7-dihyd ro-[5H]-pyrrolo[1,2-a] imidazole} and its metabolite, SK&F 105561 nyl) -3-(4-pyridyl)-6,7-dihydro-[5H]-pyrrolo[1,2-a] imidazole} are dual 5-l ipoxygenase (5-LO) and cycloxygenase (CO) inhibitors with potent antii nflammatory and cytokine (IL-1/TNF) suppressive activities. The anti-i nflammatory activity of SK&F 105809 and its metabolite were evaluated in an antigen-specific murine model of delayed type hypersensitivity ( DTH) response, where they were found to affect only the inflammatory a nd not the induction phase of this response. In contrast, these compou nds and other pyridinyl imidazoles (SK&F 86002 and its analog, SK&F 10 4351) exhibited no immunosuppressive activity under conditions where t he macrolide rapamycin and the corticosteroid dexamethasone abrogated both the cellular and humoral immune responses. Thus, the ability of p yridinyl imidazoles to attenuate independently the inflammatory compon ents of the disease without causing generalized immunosuppression enha nces their profile as candidates for therapy of chronic inflammatory d iseases, specifically those mediated by cytokines (e.g. IL-1, TNF) and eicosanoids.