RESUMEN
We describe a series of dehydrophenylalanine derivatives where the Z isomers are potent VLA-4 antagonists but are subject to rapid biliary clearance and the E isomers have poor activity but have a slower rate of clearance. These configurationally constrained molecules have led to the design of a novel class of benzodiazepine VLA-4 antagonists.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Fenilalanina/análogos & derivados , Fenilalanina/química , Fenilalanina/farmacología , Animales , Benzodiazepinas/química , Benzodiazepinas/farmacología , Sistema Biliar/metabolismo , Diseño de Fármacos , Concentración 50 Inhibidora , Isomerismo , Fenilalanina/farmacocinética , Ratas , Relación Estructura-ActividadRESUMEN
SAR studies aimed at improving the rate of clearance by the incorporation of a 3,4-diamino-3-cyclobutene-1,2-dione group as an amino acid isostere in a series of VLA-4 integrin antagonists are described.
Asunto(s)
Antialérgicos/antagonistas & inhibidores , Ciclobutanos/síntesis química , Ciclobutanos/farmacología , Integrinas/antagonistas & inhibidores , Receptores Mensajeros de Linfocitos/antagonistas & inhibidores , Aminas/química , Animales , Integrina alfa4beta1 , Integrina beta1 , Tasa de Depuración Metabólica , Ratas , Receptores de Antígeno muy Tardío , Relación Estructura-ActividadRESUMEN
SAR studies aimed at improving the rate of clearance of a series of VLA-4 integrin antagonists by the introduction of a 1,3,5-triazine as an amide isostere are described.
Asunto(s)
Integrina alfa4beta1/antagonistas & inhibidores , Fenilalanina/química , Fenilalanina/farmacología , Triazinas/química , Triazinas/farmacología , Fenilalanina/análogos & derivados , Relación Estructura-ActividadRESUMEN
The SAR studies to optimise both potency and rate of clearance in the rat for a series of pyrimidine and pyridine based VLA-4 antagonists are described.