The inhibition of glutaminyl cyclase (QC) may provide a promising strategy for 
the treatment of early Alzheimer's disease (AD) by reducing the amount of the 
toxic pyroform of β-amyloid (AβΝ3pE) in the brains of AD patients. In this work, 
we identified potent QC inhibitors with subnanomolar IC50 values that were up to 
290-fold higher than that of PQ912, which is currently being tested in Phase II 
clinical trials. Among the tested compounds, the cyclopentylmethyl derivative 
(214) exhibited the most potent in vitro activity (IC50 = 0.1 nM), while 
benzimidazole (227) showed the most promising in vivo efficacy, selectivity and 
druggable profile. 227 significantly reduced the concentration of pyroform Aβ 
and total Aβ in the brain of an AD animal model and improved the alternation 
behavior of mice during Y-maze tests. The crystal structure of human QC (hQC) in 
complex with 214 indicated tight binding at the active site, supporting that the 
specific inhibition of QC results in potent in vitro and in vivo activity. 
Considering the recent clinical success of donanemab, which targets AβΝ3pE, 
small molecule-based QC inhibitors may also provide potential therapeutic 
options for early-stage AD treatment.