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Vol. 293, Issue 1, 281-288, April 2000
Departments of Pulmonary Pharmacology (D.C.U., R.R.O., C.J.K.,
E.F.W., D.C.C., S.B., D.W.P.H., D.E.G.), Medicinal Chemistry
(J.L.A.), Bone Biology (J.C.L.), and Safety Assessment (H.C.T.),
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania
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
IC50 of 44 nM for inhibition of recombinant purified human
p38
. In lipopolysaccharide-stimulated human peripheral blood
monocytes, SB 239063 inhibited interleukin-1 and tumor necrosis
factor- production (IC50 values = 0.12 and 0.35 µM, 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- production by SB 239063 (ED50 = 5.8 mg/kg p.o.).
Antiallergic activity was demonstrated by essential abolition (~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
(~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 D4 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 µM) 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.
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