RESUMEN
A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.
Asunto(s)
Asma/tratamiento farmacológico , Benzoatos/administración & dosificación , Benzoatos/farmacocinética , Integrina alfa4beta1/antagonistas & inhibidores , Pirrolidinas/química , Pirrolidinonas/administración & dosificación , Pirrolidinonas/farmacocinética , Administración Oral , Animales , Benzoatos/química , Permeabilidad de la Membrana Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Activación Enzimática/efectos de los fármacos , Éteres de Hidroxibenzoatos , Riñón/citología , Masculino , Ratones , Ratones Endogámicos BALB C , Conformación Molecular , Pirrolidinonas/química , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
A novel series of 2-(1,2,4-oxadiazol-5-yl)-1H-indole derivatives as nociceptin/orphanin FQ (N/OFQ) receptor antagonists was discovered. Systematic modification of our original lead by changing the pendant functional groups, linker, heterocyclic core, and basic side chain revealed the structure-activity requirements for this novel template and resulted in the identification of more potent analog with improved potency as compared to the parent compound.