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
A series of 3-aryl-4-hydroxyquinolin-2(1H)-ones with fatty acid synthase inhibitory activity was prepared. Starting from a derivative with an IC(50) = 1.4 microM, SAR studies led to compounds with more than 70-fold increase in potency (IC(50) < 20 nM).
Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Ácido Graxo Sintases/antagonistas & inibidores , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacologia , Quinolinas/química , Quinolinas/farmacologia , Animais , Inibidores Enzimáticos/química , Ácido Graxo Sintases/metabolismo , Humanos , Hidroxiquinolinas/síntese química , Malonatos/química , Micro-Ondas , Estrutura Molecular , Quinolinas/síntese química , Ratos , Relação Estrutura-AtividadeRESUMO
Catalytic asymmetric cross-coupling reactions between aldehydes and N-acylimines have been discovered that employ thiazolylalanine derivatives as catalysts. Alkylation of the thiazolyl moiety, followed by in situ generation of the derived thiazolium ylide using a tertiary amine base, leads to the active catalyst. alpha-Amidoketone products are isolated in up to 90% yield with up to 87% enantiomeric excess (>98% ee after a single recrystallization). The use of a hindered base to suppress product racemization was stimulated by a mechanistic study that revealed an isotope effect on the racemization rate of the product.