Abstract
We investigated in vivo efficacies of the newly synthesized VLA-4 antagonist Compound A {trans-4-[1-[[2,5-Dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid} on Ascaris antigen-induced airway inflammation and hyperresponsiveness in a murine asthmatic model. Oral administration of Compound A significantly inhibited eosinophil infiltration into BALF and airway hyperresponsiveness 48 h after the antigen challenge. Histologic analysis of the lung sections confirmed the BALF result and revealed suppression of edema and mucus hyperplasia at 8 and 48 h after the challenge, respectively. These findings clearly show that orally active Compound A has therapeutic potential for treatment of asthma.
MeSH terms
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Acetylcholine / pharmacology
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Administration, Oral
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Asthma / drug therapy*
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Asthma / pathology
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Asthma / physiopathology
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Bronchoalveolar Lavage Fluid / cytology
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Cyclohexanecarboxylic Acids / administration & dosage
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Cyclohexanecarboxylic Acids / pharmacology
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Cyclohexanecarboxylic Acids / therapeutic use*
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Disease Models, Animal
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Edema / drug therapy
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Eosinophils / drug effects
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Female
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Inflammation / drug therapy
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Integrin alpha4beta1 / antagonists & inhibitors*
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Lung / drug effects*
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Lung / physiology*
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Lung / physiopathology
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Mice
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Pyrrolidines / administration & dosage
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Pyrrolidines / pharmacology
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Pyrrolidines / therapeutic use*
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Respiratory System / drug effects*
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Respiratory System / pathology
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Respiratory System / physiopathology
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Time Factors
Substances
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Anti-Inflammatory Agents, Non-Steroidal
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Cyclohexanecarboxylic Acids
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Integrin alpha4beta1
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Pyrrolidines
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trans-4-(1-((2,5-dichloro-4-(1-methyl-3-indolylcarboxyamide)phenyl)acetyl)-(4S)-methoxy-(2S)-pyrrolidinylmethoxy)cyclohexanecarboxylic acid
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Acetylcholine