RESUMEN
Novel bicyclic adenosine A(2A) antagonists with an aminoquinazoline moiety were designed and synthesized. The optimization of the initial lead compound based on in vitro and in vivo activity has led to the discovery of a potent and selective class of adenosine A(2A) antagonists. The structure-activity relationships of this novel series of bicyclic aminoquinazoline derivatives as adenosine A(2A) antagonists are described in detail.
Asunto(s)
Antagonistas del Receptor de Adenosina A2/química , Quinazolinas/química , Receptor de Adenosina A2A/química , Antagonistas del Receptor de Adenosina A2/síntesis química , Antagonistas del Receptor de Adenosina A2/farmacocinética , Animales , Sitios de Unión , Diseño de Fármacos , Semivida , Humanos , Concentración 50 Inhibidora , Simulación del Acoplamiento Molecular , Estructura Terciaria de Proteína , Quinazolinas/síntesis química , Quinazolinas/farmacocinética , Ratas , Receptor de Adenosina A2A/metabolismo , Relación Estructura-ActividadRESUMEN
Fused oxadiazines (3) were discovered as selective and orally bioavailable γ-secretase modulators (GSMs) based on the structural framework of oxadiazoline GSMs. Although structurally related, initial modifications showed that structure-activity relationships (SARs) did not translate from the oxadiazoline to the oxadiazine series. Subsequent SAR studies on modifications at the C3 and C4 positions of the fused oxadiazine core helped to identify GSMs such as compounds 8r and 8s that were highly efficacious in vitro and in vivo in a number of animal models with highly desirable physical and pharmacological properties. Further improvements of in vitro activity and selectivity were achieved by the preparation of fused morpholine oxadiazines. The shift in specificity of APP cleavage rather than a reduction in overall γ-secretase activity and the lack of changes in substrate accumulation and Notch processing as observed in the animal studies of compound 8s confirm that the oxadiazine series of compounds are potent GSMs.
RESUMEN
Cyclic hydroxyamidines were designed and validated as isosteric replacements of the amide functionality. Compounds with these structural motifs were found to be metabolically stable and to possess highly desirable pharmacokinetic profiles. These designs were applied in the identification of γ-secretase modulators leading to highly efficacious agents for reduction of central nervous system Aß(42) in various animal models.
