EFFECTS OF PYRIDINYL IMIDAZOLE COMPOUNDS ON MURINE TNF-ALPHA PRODUCTION

The effects of SK&F 86002 and other pyridinyl imidazole compounds on m urine cytokine production were investigated. In vitro, SK&F 86002 inhi bited LPS stimulated TNF-alpha production by the RAW 264.7 cell line a nd by oil elicited peritoneal macrophages with an IC50 of 5 muM. In ge neral, the activity was reflective of previous results obtained with h uman monocytes as SK&F 86002 and its analogs demonstrated identical ra nk order potency for TNF-alpha inhibition in both species. These compo unds also inhibited TNF-alpha in vivo in a murine model of endotoxin s hock. Following oral administration, SK&F 86002 and its analogs reduce d serum TNF-alpha levels by > 80% and afforded 100% protection from le thality. In contrast, tenidap, a novel anti-inflammatory drug, had min imal to no effect on murine TNF-alpha production in the same assays. T hese data further extend the pharmacological profile of the pyridinyl imidazoles by demonstrating that these compounds potently inhibit muri ne TNF-alpha production both in vitro and in vivo.