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.
Subject(s)
Integrin alpha4beta1/antagonists & inhibitors , Phenylalanine/analogs & derivatives , Phenylalanine/pharmacology , Animals , Calcium/chemistry , Calcium/pharmacology , Chemotaxis, Leukocyte/drug effects , Dogs , Eosinophils/drug effects , Half-Life , Humans , Inhibitory Concentration 50 , Isonicotinic Acids/blood , Isonicotinic Acids/chemical synthesis , Isonicotinic Acids/pharmacokinetics , Isonicotinic Acids/pharmacology , Jurkat Cells , Macaca mulatta , Manganese/chemistry , Manganese/pharmacology , Phenylalanine/blood , Phenylalanine/pharmacokinetics , Protein Binding , Rats , Rats, Sprague-Dawley , Vascular Cell Adhesion Molecule-1/metabolismABSTRACT
A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.
