RESUMEN
Starting with the molecular scaffold of the DA(2)/ß(2) dual agonist sibenadet (Viozan™), a number of molecular changes were incorporated, which were designed to increase the potency and selectivity of the target molecule, and improve its pharmacokinetics. Through this process a novel, high potency, full ß(2)-agonist with high selectivity and long duration capable of being dosed once daily has been discovered.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 2/química , Broncodilatadores/química , Receptores Adrenérgicos beta 2/química , Tiazoles/química , Agonistas de Receptores Adrenérgicos beta 2/síntesis química , Agonistas de Receptores Adrenérgicos beta 2/farmacocinética , Animales , Broncodilatadores/síntesis química , Broncodilatadores/farmacocinética , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Cobayas , Receptores Adrenérgicos beta 2/metabolismo , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/farmacocinéticaRESUMEN
Selective activation of peripheral cannabinoid CB1 receptors has the potential to become a valuable therapy for chronic pain conditions as long as central nervous system effects are attenuated. A new class of cannabinoid ligands was rationally designed from known aminoalkylindole agonists and showed good binding and functional activities at human CB1 and CB2 receptors. This has led to the discovery of a novel CB1/CB2 dual agonist, naphthalen-1-yl-(4-pentyloxynaphthalen-1-yl)methanone (13), which displays good oral bioavailability, potent antihyperalgesic activity in animal models, and limited brain penetration.