Abstract
A series of isonicotinoyl-(L)-aminophenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. These compounds exhibit subnanomolar binding affinity to VLA-4 and significant off-rates. The interplay between off-rate, protein binding and pharmacokinetics is discussed.
MeSH terms
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Animals
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Calcium / chemistry
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Calcium / pharmacology
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Chemotaxis, Leukocyte / drug effects
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Dogs
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Eosinophils / drug effects
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Half-Life
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Humans
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Inhibitory Concentration 50
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Integrin alpha4beta1 / antagonists & inhibitors*
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Isonicotinic Acids / blood
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Isonicotinic Acids / chemical synthesis
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Isonicotinic Acids / pharmacokinetics
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Isonicotinic Acids / pharmacology
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Jurkat Cells
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Macaca mulatta
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Manganese / chemistry
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Manganese / pharmacology
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Phenylalanine / analogs & derivatives*
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Phenylalanine / blood
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Phenylalanine / pharmacokinetics
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Phenylalanine / pharmacology*
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Protein Binding
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Rats
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Rats, Sprague-Dawley
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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Integrin alpha4beta1
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Isonicotinic Acids
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Vascular Cell Adhesion Molecule-1
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Manganese
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Phenylalanine
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Calcium