SB 239063, a potent p38 MAP kinase inhibitor, reduces inflammatory cytokine production, airways eosinophil infiltration, and persistence

The anti-inflammatory/antiallergic activity of a novel second-generation p3 8 mitogen-activated protein kinase inhibitor, SB 239063 [trans-1-(4-hydroxy cyclohexyl)-4-(4-fluorophenyl methoxypyridimidin-4-yl)imidazole], was inves tigated in vivo and in vitro. SB 239063 had an IC50 of 44 nM for inhibition of recombinant purified human p38 alpha. In lipopolysaccharide-stimulated human peripheral blood monocytes, SB 239063 inhibited interleukin-1 and tum or necrosis factor-alpha production (IC50 values = 0.12 and 0.35 mu M, resp ectively). A role for p38 kinase in cytokine-associated inflammation in the mouse was shown by p38 activation in the lung and inhibition of lipopolysa ccharide-induced tumor necrosis factor-a production by SB 239063 (ED50 = 5. 8 mg/kg p.o.). Antiallergic activity was demonstrated by essential abolitio n (similar to 93% inhibition) of inhaled ovalbumin (OA)-induced airway eosi nophilia by SB 239063 (12 mg/kg p.o.), measured by bronchoalveolar lavage ( BAL) in OA-sensitized mice. In addition, p38 kinase was found by Western an alysis to be activated in guinea pig lung. Administration of SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced (similar to 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h a fter antigen. SB 239063 (10 mg/kg b.i.d. p.o.) administered after leukotrie ne D-4 inhalation, reduced by 60% the persistent airway eosinophilia seen a t 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL wa s increased by SB 239063 (1-10 mu M) in the presence of interleukin-5. Thes e results indicate that SE 239063 is a potent inhibitor of inflammatory cyt okine production, inhibits eosinophil recruitment, in addition to enhancing apoptosis of these cells. Collectively, the results support the potential utility of p38 kinase inhibitors, such as SE 239063, for the treatment of a sthma and other inflammatory disorders.