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.
Olivera
D L
DL
Department of Cellular Biochemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
Laydon
J T
JT
Hillegass
L
L
Badger
A M
AM
Lee
J C
JC
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D000078183:Oxindoles; D012772:Shock, Septic / Q000188:drug therapy*; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007093:Imidazoles; D007211:Indoles; D008070:Lipopolysaccharides; D000078183:Oxindoles; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; C062866:tenidap; C052026:6-(4-fluorophenyl)-2,3-dihydro-5-(4-pyridinyl)imidazo(2,1-b)thiazole