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Departments of 1 Pulmonary Pharmacology, 2 Bone and Cartilage Biology, 3 Cardiovascular Pharmacology, and 4 Medicinal Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406
The effects of a second
generation p38 mitogen-activated protein kinase (MAPK) inhibitor, SB
239063 [trans-1-(4-hydroxycyclohexyl)-4-(4-fluorophenyl)-5-(2-methoxypyridimidin-4-yl)imidazole; IC50 = 44 nM vs. p38
], were assessed in models
that represent different pathological aspects of chronic obstructive
pulmonary disease (COPD) [airway neutrophilia, enhanced cytokine
formation and increased matrix metalloproteinase (MMP)-9 activity] and
in a model of lung fibrosis. Airway neutrophil infiltration and
interleukin (IL)-6 levels, assessed by bronchoalveolar lavage 48 h
after lipopolysaccharide (LPS) inhalation, were inhibited dose
dependently by 3-30 mg/kg of SB 239063 given orally twice a
day. In addition, SB 239063 (30 mg/kg orally) attenuated IL-6
bronchoalveolar lavage fluid concentrations (>90% inhibition) and
MMP-9 activity (64% inhibition) assessed 6 h after LPS exposure.
In guinea pig cultured alveolar macrophages, SB 239063 inhibited
LPS-induced IL-6 production (IC50 of 362 nM). In a
bleomycin-induced pulmonary fibrosis model in rats, treatment with SB
239063 (2.4 or 4.8 mg/day via osmotic pump) significantly
inhibited bleomycin-induced right ventricular hypertrophy (indicative
of secondary pulmonary hypertension) and increases in lung
hydroxyproline synthesis (indicative of collagen synthesis and
fibrosis). Therefore, SB 239063 demonstrates activity against a range
of sequelae commonly associated with COPD and fibrosis, supporting the
therapeutic potential of p38 MAPK inhibitors such as SB 239063 in
chronic airway disease.
chronic obstructive pulmonary disease; interleukin-6; bleomycin; alveolar macrophage; mitogen-activated protein kinase; matrix metalloproteinase-9
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