PHARMACOLOGICAL PROFILE OF SB-203580, A SELECTIVE INHIBITOR OF CYTOKINE SUPPRESSIVE BINDING PROTEIN P38 KINASE, IN ANIMAL-MODELS OF ARTHRITIS, BONE-RESORPTION, ENDOTOXIN-SHOCK AND IMMUNE FUNCTION/

SB 203580 -(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4- pyridyl)i midazole], a selective cytokine suppressive binding protein/p38 kinase inhibitor, was evaluated in several models of cytokine inhibition and inflammatory disease. It was demonstrated clearly to be a potent inhi bitor of inflammatory cytokine production in vivo in both mice and rat s with IC50 values of 15 to 25 mg/kg. SE 203580 possessed therapeutic activity in collagen-induced arthritis in DBA/LACJ mice with a dose of 50 mg/kg resulting in significant inhibition of paw inflammation and serum amyloid protein levels. Antiarthritic activity was also observed in adjuvant-induced arthritis in the Lewis rat when SE 203580 was adm inistered p.o. at 30 and 60 mg/kg. Evidence for disease-modifying acti vity in this model was indicated by an improvement in bone mineral den sity and by histological evaluation. Additional evidence for beneficia l effects on bone resorption was provided in the fetal rat long bone a ssay in which SE 203580 inhibited Ca-45 release with an IC50 of 0.6 mu M. In keeping with the inhibitory effects on lipopolysaccharide-induc ed tumor necrosis factor-alpha in mice, SE 203580 was found to reduce mortality in a murine model of endotoxin-induced shock. In immune func tion studies in mice treated with SE 203580 (60 mg/kg/day for 2 weeks) , there was some suppression of an antibody response to ovalbumin, whe reas cellular immune functions measured ex vivo were unaffected. This novel profile of activity strongly suggests that cytokine inhibitors c ould provide significant benefit in the therapy of chronic inflammator y disease.