RESUMEN
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.
Asunto(s)
Secretasas de la Proteína Precursora del Amiloide/metabolismo , Piperazinas/química , Pirimidinas/química , Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Péptidos beta-Amiloides/antagonistas & inhibidores , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/fisiología , Línea Celular Tumoral , Células HeLa , Humanos , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/metabolismo , Piperazinas/farmacología , Pirimidinas/farmacologíaRESUMEN
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).
Asunto(s)
Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Ácido Graso Sintasas/antagonistas & inhibidores , Hidroxiquinolinas/química , Hidroxiquinolinas/farmacología , Quinolinas/química , Quinolinas/farmacología , Animales , Inhibidores Enzimáticos/química , Ácido Graso Sintasas/metabolismo , Humanos , Hidroxiquinolinas/síntesis química , Malonatos/química , Microondas , Estructura Molecular , Quinolinas/síntesis química , Ratas , Relación Estructura-ActividadRESUMEN
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.
