RESUMEN
A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.
Asunto(s)
Antiinflamatorios/química , Isoindoles/química , Subtipo EP4 de Receptores de Prostaglandina E/agonistas , Animales , Antiinflamatorios/farmacocinética , Antiinflamatorios/uso terapéutico , Células Sanguíneas/citología , Células Sanguíneas/efectos de los fármacos , Células Sanguíneas/metabolismo , Dinoprostona/química , Dinoprostona/uso terapéutico , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Concentración 50 Inhibidora , Isoindoles/farmacocinética , Isoindoles/uso terapéutico , Lipopolisacáridos/farmacología , Dolor/tratamiento farmacológico , Dolor/patología , Dolor/veterinaria , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/metabolismo , Ratas , Subtipo EP4 de Receptores de Prostaglandina E/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.