The anti-inflammatory/
antiallergic activity of a novel second-generation
p38 mitogen-activated protein kinase inhibitor,
SB 239063[trans-1-(4-hydroxycyclohexyl) -4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)
imidazole], was investigated in vivo and in vitro.
SB 239063 had an IC(50) of 44 nM for inhibition of recombinant purified human p38alpha. In
lipopolysaccharide-stimulated human peripheral blood monocytes,
SB 239063 inhibited
interleukin-1 and
tumor necrosis factor-alpha production (IC(50) values = 0.12 and 0.35 microM, respectively). A role for p38
kinase in
cytokine-associated
inflammation in the mouse was shown by p38 activation in the lung and inhibition of
lipopolysaccharide-induced
tumor necrosis factor-alpha production by
SB 239063 (ED(50) = 5.8 mg/kg p.o.).
Antiallergic activity was demonstrated by essential abolition (approximately 93% inhibition) of inhaled
ovalbumin (OA)-induced airway
eosinophilia 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 analysis to be activated in guinea pig lung. Administration of
SB 239063 (10 or 30 mg/kg p.o.) in conscious guinea pigs markedly reduced ( approximately 50% inhibition) OA-induced pulmonary eosinophil influx, measured by BAL 24 h after
antigen.
SB 239063 (10 mg/kg b.i.d. p.o.) administered after
leukotriene D(4) inhalation, reduced by 60% the persistent airway
eosinophilia seen at 4 days. Apoptosis of cultured eosinophils isolated from guinea pig BAL was increased by
SB 239063 (1-10 microM) in the presence of
interleukin-5. These results indicate that
SB 239063 is a potent inhibitor of inflammatory
cytokine 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
SB 239063, for the treatment of
asthma and other inflammatory disorders.