RESUMEN
We have designed and synthesized a series of heterocyclic bioisosteres for an anilide based on molecular modeling. Excellent potency was retained in the benzoxazole and the benzimidazole derivatives, where a hydrogen bond acceptor is appropriately positioned to mimic the amide bond oxygen. The deletion of the hydrogen bond donor (N-H) led to improved lipophilicity and bioavailability. In the process, 9a was identified as a potent, specific, and bioavailable VLA-4 antagonist, while 9c was found to be a potent and bioavailable dual antagonist of VLA-4 and alpha(4)beta(7).
Asunto(s)
Anilidas/química , Benzoxazoles/química , Integrina alfa4beta1/antagonistas & inhibidores , Animales , Disponibilidad Biológica , Enlace de Hidrógeno , RatasRESUMEN
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.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Sulfonamidas/síntesis química , Sulfonamidas/farmacocinética , Administración Oral , Animales , Furanos/síntesis química , Furanos/química , Furanos/farmacocinética , Furanos/farmacología , Humanos , Concentración 50 Inhibidora , Ligandos , Peso Molecular , Fenilalanina/síntesis química , Fenilalanina/farmacocinética , Fenilalanina/farmacología , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Especificidad por Sustrato , Sulfonamidas/sangre , Sulfonamidas/química , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
A series of N-arylated phenylalanine derivatives has been synthesized and has been shown to be potent inhibitors of the integrin VLA-4. N-phenyl and N-heteroaryl derivatives with hydrogen bond acceptors in the meta position demonstrated low nanomolar activity against VLA-4.
Asunto(s)
Integrinas/antagonistas & inhibidores , Fenilalanina/farmacología , Receptores Mensajeros de Linfocitos/antagonistas & inhibidores , Integrina alfa4beta1 , Estructura Molecular , Fenilalanina/análogos & derivados , Fenilalanina/síntesis química , Relación Estructura-ActividadRESUMEN
Acylated beta-amino acids are described as potent, specific and orally bioavailable antagonists of VLA-4. The initial lead was identified from a combinatorial library. Subsequent optimization using a traditional medicinal chemistry approach led to significant improvement in potency (up to 8-fold) while maintaining good pharmacokinetic properties.
Asunto(s)
Aminoácidos/síntesis química , Mediadores de Inflamación/síntesis química , Integrina alfa4beta1/antagonistas & inhibidores , Acilación , Administración Oral , Aminoácidos/metabolismo , Aminoácidos/farmacocinética , Animales , Disponibilidad Biológica , Técnicas Químicas Combinatorias , Evaluación Preclínica de Medicamentos , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/farmacocinética , Tasa de Depuración Metabólica , Unión Proteica , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
N-(3,5-Dichlorophenylsulfonyl)-(R)-thioprolyl biarylalanine 10a has been identified as a potent and specific antagonist of the alpha(4)beta(1) integrin. Altering the configuration of thioproline from R to S led to a series of dual antagonists of alpha(4)beta(1) and alpha(4)beta(7), and the N-acetyl analogue 8b was found to be the most potent dual antagonist. A binding site model for alpha(4)beta(1) and alpha(4)beta(7) is proposed to explain the structure-activity relationship.