RESUMO
By focusing on the P1 portion of the piperidine beta-sulfone ligands we identified a motif that induces selectivity and resulted in a series of TACE inhibitors that demonstrated excellent in vitro potency against isolated TACE enzyme and excellent selectivity over MMPs 1, 2, 9, 13, and 14.
Assuntos
Proteínas ADAM/antagonistas & inibidores , Proteínas ADAM/química , Inibidores de Proteases/química , Inibidores de Proteases/isolamento & purificação , Proteína ADAM17 , Cristalografia por Raios X , Ligantes , Metaloendopeptidases/antagonistas & inibidores , Piperidinas/química , Inibidores de Proteases/farmacologia , Sulfonas/químicaRESUMO
BACE1 is an aspartyl protease responsible for cleaving amyloid precursor protein to liberate Abeta, which aggregates leading to plaque deposits implicated in Alzheimer's disease. We have identified small-molecule acylguanidine inhibitors of BACE1. Crystallographic studies show that these compounds form unique hydrogen-bonding interactions with the catalytic site aspartic acids and stabilize the protein in a flap-open conformation. Structure-based optimization led to the identification of potent analogs, such as 10d (BACE1 IC(50) = 110 nM).
