RESUMO
Synthesis and SAR studies of novel aryl triazoles as gamma secretase modulators (GSMs) are presented in this communication. Starting from our aryl triazole leads, optimization studies were continued and the series progressed towards novel amides and lactams. Triazole 57 was identified as the most potent analog in this series, displaying single-digit nanomolar Aß42 IC(50) in cell-based assays and reduced affinity for the hERG channel.
Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Transativadores/metabolismo , Triazóis/farmacologia , Amidas/química , Amidas/farmacologia , Peptídeos beta-Amiloides , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Concentração Inibidora 50 , Lactamas , Relação Estrutura-Atividade , Regulador Transcricional ERG , Triazóis/químicaRESUMO
Synthesis, SAR, and evaluation of aryl triazoles as novel gamma secretase modulators (GSMs) are presented in this communication. Starting from the literature and in-house leads, we evaluated a range of five-membered heterocycles as replacements for olefins commonly found in non-acid GSMs. 1,2,3-C-aryl-triazoles were identified as suitable replacements which exhibited good modulation of γ-secretase activity, excellent pharmacokinetics and good central lowering of Aß42 in Sprague-Dawley rats.
