Effects of pyridinyl imidazole compounds on murine TNF-alpha production

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-alpha production by the RAW 264.7 cell line and by oil elicited peritoneal macrophages with an IC50 of 5 microM. 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-alpha inhibition in both species. These compounds also inhibited TNF-alpha in vivo in a murine model of endotoxin shock. Following oral administration, SK&F 86002 and its analogs reduced serum TNF-alpha 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-alpha 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-alpha production both in vitro and in vivo.