RESUMEN
A novel alpha7 nAChR agonist, N-[(3R,5R)-1-azabicyclo[3.2.1]oct-3-yl]furo[2,3-c]pyridine-5-carboxamide (3a, PHA-709829), has been identified for the potential treatment of cognitive deficits in schizophrenia. The compound shows potent and selective alpha7 in vitro activity, excellent brain penetration, good rat oral bioavailability and robust in vivo efficacy in a rat auditory sensory gating model.
Asunto(s)
Compuestos de Azabiciclo/farmacología , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Compuestos de Azabiciclo/síntesis química , Compuestos de Azabiciclo/química , Benzamidas/farmacología , Proteínas Sanguíneas/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Perros , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Microsomas Hepáticos/efectos de los fármacos , Conformación Molecular , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/química , Piridinas/síntesis química , Piridinas/química , Quinuclidinas/farmacología , Ratas , Receptores Muscarínicos/efectos de los fármacos , Estereoisomerismo , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
A novel set of azabicyclic aryl amides have been identified as potent and selective agonists of the alpha7 nAChR. A two-pronged approach was taken to improve the potential hERG liability of previously disclosed alpha7 nAChR agonist, PNU-282,987, while maintaining the compound's other desirable pharmacological properties. The first approach involved further exploration of the aryl carboxylic acid fragment of PNU-282,987, while the second approach focused on modification of the azabicyclic amine portion of PNU-282,987. The best compounds from each series are characterized by rapid brain penetration, good oral bioavailability in rat, and demonstrate in vivo efficacy in a rat P50 auditory sensory gating assay. At least one analog from each series (1h, 1o, 2a, 9a, and 18a) shows an improved hERG safety profile over PNU-282,987.