RESUMO
The development of a novel series of piperazinyl pyrimidines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a screening hit provided a series of potent gamma-secretase modulators with >180-fold in vitro selectivity over inhibition of Notch cleavage.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Piperazinas/química , Pirimidinas/química , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/fisiologia , Linhagem Celular Tumoral , Células HeLa , Humanos , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Piperazinas/farmacologia , Pirimidinas/farmacologiaRESUMO
The development of a novel series of purines as gamma-secretase modulators for potential use in the treatment of Alzheimer's disease is disclosed herein. Optimization of a previously disclosed pyrimidine series afforded a series of potent purine-based gamma-secretase modulators with 300- to 2000-fold in vitro selectivity over inhibition of Notch cleavage and that selectively reduces Alphabeta42 in an APP-YAC transgenic mouse model.