Effects of pyridinyl imidazole compounds on murine TNF-α production

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Abstract
The effects of SK&F 86002 and other pyridinyl imidazole compounds on murine cytokine production were investigated.In vitro, SK&F 86002 inhibited LPS stimulated TNF-α production by the RAW 264.7 cell line and by oil elicited peritoneal macrophages with an IC50 of 5μM. In general, the activity was reflective of previous results obtained with human monocytes as SK&F 86002 and its analogs demonstrated identical rank order potency for TNF-α inhibition in both species. These compounds also inhibited TNF-αin vivo in a murine model of endotoxin shock. Following oral administration, SK&F 86002 and its analogs reduced serum TNF-α levels by >80% and afforded 100% protection from lethality. In contrast, tenidap, a novel anti-inflammatory drug, had minimal to no effect on murine TNF-α production in the same assays. These data further extend the pharmacological profile of the pyridinyl imidazoles by demonstrating that these compounds potently inhibit murine TNF-α production bothin vitro andin vivo.