RESUMEN
We describe the discovery and optimization of a novel series of benzofuran EP(1) antagonists, leading to the identification of 26d, a novel nonacidic EP(1) antagonist which demonstrated efficacy in preclinical models of chronic inflammatory pain.
Asunto(s)
Antiinflamatorios no Esteroideos/química , Benzofuranos/química , Subtipo EP1 de Receptores de Prostaglandina E/antagonistas & inhibidores , Animales , Antiinflamatorios no Esteroideos/farmacocinética , Antiinflamatorios no Esteroideos/uso terapéutico , Benzofuranos/farmacocinética , Benzofuranos/uso terapéutico , Línea Celular , Modelos Animales de Enfermedad , Perros , Evaluación Preclínica de Medicamentos , Dolor/tratamiento farmacológico , Ratas , Subtipo EP1 de Receptores de Prostaglandina E/metabolismo , Relación Estructura-ActividadRESUMEN
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP(1) receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain.