RESUMEN
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.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Fenilalanina/farmacología , Animales , Calcio/química , Calcio/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Perros , Eosinófilos/efectos de los fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Ácidos Isonicotínicos/sangre , Ácidos Isonicotínicos/síntesis química , Ácidos Isonicotínicos/farmacocinética , Ácidos Isonicotínicos/farmacología , Células Jurkat , Macaca mulatta , Manganeso/química , Manganeso/farmacología , Fenilalanina/sangre , Fenilalanina/farmacocinética , Unión Proteica , Ratas , Ratas Sprague-Dawley , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
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.
