RESUMEN
A new series of thienopyrimidinones is synthesized and evaluated as selective phosphodiesterase 7 (PDE7) inhibitors for the treatment of inflammatory diseases. The modification of the substituents on thienopyrimidinone revealed that an isopropylamino group at the 2-position was favorable for aqueous solubility. The introduction of 3-pyrrolidines at the 7-position resulted in good solubility, highly potent activity, and good PDE7 selectivity. Among the synthesized compounds, compound 46 exhibited the greatest inhibition of ear edema in a phorbol ester-induced mouse model.
Asunto(s)
Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/antagonistas & inhibidores , Edema/tratamiento farmacológico , Pirimidinonas/farmacología , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 7/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Masculino , Ratones , Ratones Endogámicos ICR , Modelos Moleculares , Estructura Molecular , Ésteres del Forbol , Pirimidinonas/síntesis química , Pirimidinonas/química , Solubilidad , Relación Estructura-Actividad , Especificidad por SustratoRESUMEN
The discovery and SAR study of a new series of soluble and highly potent phosphodiesterase (PDE) 7 inhibitors are described herein. We explored a new lead compound with improved solubility, which led to the discovery of a 2-(4-pyridylamino)thieno[3,2-d]pyrimidin-4(3H)-one series. The introduction of 3-piperidines at the 7-position resulted in the significant enhancement of PDE7 activity. In particular, compound 32 also showed strong PDE7 inhibitory activity; good selectivity against PDE3, 4, and 5; and good aqueous solubility.
