Abstract
A series of isoxazolyl, oxazolyl, and thiazolylpropionic acid derivatives derived from LDV was found to be a potent antagonist of the alpha(4)beta(1) integrin. The synthesis and SAR leading up to 3-[3-(1-[-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetylamino]-3-methyl-butyl)-isoxazol-5-yl]-propionic acid (22) are reported. In an allergic mouse model, compound 22 was efficacious delivered systemically (58% inhib @ 10 mg/kg, sc) as well as by intra-tracheal instillation (ED(50)=2 microg/kg).
MeSH terms
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Animals
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Disease Models, Animal
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Humans
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Hypersensitivity / drug therapy
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Integrin alpha4beta1
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Integrins / antagonists & inhibitors*
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Isoxazoles / pharmacology*
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Jurkat Cells
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Mice
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Propionates / pharmacology*
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Receptors, Lymphocyte Homing / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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3-(3-(1-(-(3-methoxy-4-(3-o-tolyl-ureido)-phenyl)-acetylamino)-3-methyl-butyl)-isoxazol-5-yl)-propionic acid
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Integrin alpha4beta1
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Integrins
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Isoxazoles
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Propionates
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Receptors, Lymphocyte Homing