RESUMEN
Introduction of 3-substituted azetidinyl substituents onto the 4,6-diaminopyrimidine scaffold allowed the improvement of PDE4 inhibiting activities. Preliminary in vivo activity in pulmonary inflammation models is reported.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Azetidinas/química , Pirimidinas/química , Pirimidinas/farmacología , Receptor Muscarínico M3/antagonistas & inhibidores , Animales , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 4 , Femenino , Cobayas , Humanos , Ratones , Ratones Endogámicos BALB C , Pirimidinas/síntesis química , Relación Estructura-ActividadRESUMEN
The discovery and optimization of a novel class of potent CCR3 antagonists is described. Details of synthesis and SAR are given together with some ADME properties of selected compounds. An optimal balance between activities, physicochemical properties, and in vitro metabolic stability was reached by the proper choice of substituents.
Asunto(s)
Piperidinas/farmacología , Receptores de Quimiocina/antagonistas & inhibidores , Humanos , Piperidinas/síntesis química , Piperidinas/química , Receptores CCR3 , Relación Estructura-ActividadRESUMEN
SAR around 4,6-diaminopyrimidine derivatives allowed the discovery of the first potent dual M(3) antagonists and PDE4 inhibitors. Various chemical modulations around that scaffold led to the discovery of ucb-101333-3 which is characterized by the most interesting profile on both targets.