Abstract
Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.
MeSH terms
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Administration, Oral
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Animals
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Anti-Inflammatory Agents / pharmacology
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Asthma / drug therapy
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Benzoates / administration & dosage
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Benzoates / chemical synthesis
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Benzoates / pharmacology*
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Cells, Cultured
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Disease Models, Animal
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Dogs
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Female
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Inhibitory Concentration 50
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Integrin alpha4beta1 / antagonists & inhibitors*
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Mice
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Mice, Inbred BALB C
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Permeability
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Pyrroles / administration & dosage
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Pyrroles / chemical synthesis
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Pyrroles / pharmacology*
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Rats
Substances
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4-(1-(3-chloro-4-(N'-(5-fluoro-2-methylphenyl)ureido)phenylacetyl)-(4S)-fluoro-(2S)-pyrrolidinylmethoxy)benzoic acid
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Anti-Inflammatory Agents
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Benzoates
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Integrin alpha4beta1
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Pyrroles