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Publication Abstract from PubMed

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 beta-amyloid (AbetaNu3pE) 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 Abeta and total Abeta 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 AbetaNu3pE, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment.

Discovery of highly potent human glutaminyl cyclase (QC) inhibitors as anti-Alzheimer's agents by the combination of pharmacophore-based and structure-based design.,Van Manh N, Hoang VH, Ngo VTH, Ann J, Jang TH, Ha JH, Song JY, Ha HJ, Kim H, Kim YH, Lee J, Lee J Eur J Med Chem. 2021 Dec 15;226:113819. doi: 10.1016/j.ejmech.2021.113819. Epub, 2021 Sep 8. PMID:34536669^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.