Abstract
The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.
MeSH terms
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Amino Acids
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Animals
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Antibodies, Monoclonal / immunology
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Antigens, Helminth / immunology*
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Ascaris / immunology
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Asthma / drug therapy
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Asthma / pathology
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Aza Compounds / chemical synthesis
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Aza Compounds / chemistry
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Aza Compounds / pharmacology*
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Bronchi / immunology
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Bronchi / physiology
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Disease Models, Animal
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Hypersensitivity / immunology
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Hypersensitivity / pathology
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Integrin alpha4beta1 / antagonists & inhibitors*
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Integrins / antagonists & inhibitors*
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Molecular Conformation
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Molecular Structure
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Phenylalanine / chemistry
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Sheep
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry
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Sulfonamides / pharmacology*
Substances
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Amino Acids
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Antibodies, Monoclonal
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Antigens, Helminth
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Aza Compounds
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Integrin alpha4beta1
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Integrins
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Sulfonamides
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integrin alpha4beta7
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Phenylalanine