RESUMO
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.
Assuntos
Antagonistas do Receptor A2 de Adenosina/química , Quinazolinas/química , Receptor A2A de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/síntese química , Antagonistas do Receptor A2 de Adenosina/farmacocinética , Animais , Sítios de Ligação , Desenho de Fármacos , Meia-Vida , Humanos , Concentração Inibidora 50 , Simulação de Acoplamento Molecular , Estrutura Terciária de Proteína , Quinazolinas/síntese química , Quinazolinas/farmacocinética , Ratos , Receptor A2A de Adenosina/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Amidinas/síntese química , Secretases da Proteína Precursora do Amiloide/metabolismo , Oxidiazóis/síntese química , Oxazinas/síntese química , Amidinas/farmacocinética , Amidinas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Cães , Células HEK293 , Humanos , Macaca fascicularis , Masculino , Oxidiazóis/farmacocinética , Oxidiazóis/farmacologia , Oxazinas/farmacocinética , Oxazinas/farmacologia , Fragmentos de Peptídeos/metabolismo , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
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.