A small molecule VLA4 antagonist can inhibit ovalbumin induced lung inflammation

Abstract Anon-peptidyl small molecule antagonist, compound A, to non activated VLA-4 was examined,in lung ,inflammation ,induced ,by a ,single dose of ovalbumin ,challenge. Compound A presented a good pharmacokinetic property, when given intratracheally, and the blood cells from such pharmacokinetic,study showed,good receptor occupancy,of the compound,for about 8 hours. Compound,A was then tested in an ovalbumin,induced airway inflammation,model by intranasal or intravenous,route of administration. There was a dose-dependent inhibition of eosinophilia in the bronchiolar lavage fluid, when compound A was given intranasally, but not when it was given intravenously. For comparison, anti-body to VLA-4 and another compound, BIO1211, which reacts only with activated VLA-4, were examined in this system. Immunohistochemical analyses of the lung tissue substantiated the findings in the bronchiolar lavage fluid. Specific staining ofthe,major ,basic protein of eosinophils ,showed ,peribronchiolar infiltration of eosinophils. Some of these eosinophils were also positive for nitrotyrosine, suggesting activation of eosinophils ,in the lung interstitium. There was deposition of major ,basic protein and nitrotyrosine at the base of the perivascular endothelium, indicative of degranulation of eosinophils in the area. After intranasal treatment with compound A, eosinophils in the lungs and their activation products were substantially decreased, documenting,its effectiveness in inhibiting lung inflammation. Key words: VLA4 antagonist, asthma