Abstract
VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic beta-amino acids (beta-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (phi) between the amino and the carboxyl termini of the beta-aa. Compound 5 m where the beta-aa is embedded in a bicycle possesses the most preferred phi (120 degrees). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig alpha4beta1 IC50 = 54 nM, rat po F = 49%).
MeSH terms
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Biological Availability
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Bridged Bicyclo Compounds / chemical synthesis*
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Bridged Bicyclo Compounds / pharmacokinetics
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Bridged Bicyclo Compounds / pharmacology*
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Half-Life
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Humans
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Indicators and Reagents
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Integrin alpha4beta1 / antagonists & inhibitors*
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Integrins / metabolism
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Jurkat Cells
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Magnetic Resonance Spectroscopy
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Molecular Conformation
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Stereoisomerism
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Structure-Activity Relationship
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Vascular Cell Adhesion Molecule-1 / metabolism
Substances
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Bridged Bicyclo Compounds
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Indicators and Reagents
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Integrin alpha4beta1
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Integrins
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Vascular Cell Adhesion Molecule-1