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 (Aβ_Ν3pE) 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 Aβ_Ν3pE, small molecule-based QC inhibitors may also provide potential therapeutic options for early-stage AD treatment.

谷氨酰胺酰环化酶 (QC) 的抑制可能通过减少AD 患者大脑中有毒的 β-淀粉样蛋白 (Aβ _N3pE )的量来为治疗早期阿尔茨海默病 (AD) 提供有希望的策略。在这项工作中，我们确定了有效的 QC 抑制剂，其 IC ₅₀值比 PQ912 高出 290 倍，而 PQ912 目前正在 II 期临床试验中进行测试。

在测试的化合物中，环戊基甲基衍生物 ( 214 ) 表现出最有效的体外活性 (IC ₅₀  = 0.1 nM)，而苯并咪唑 ( 227 ) 表现出最有希望的体内功效、选择性和成药特性。227显着降低了AD动物模型大脑中pyroform Aβ和总Aβ的浓度，并改善了小鼠在Y迷宫测试中的交替行为。与214复合的人 QC ( h QC)的晶体结构表明在活性位点紧密结合，支持 QC 的特异性抑制导致有效的体外和体内活性。考虑到靶向 Aβ 的 donanemab 最近的临床成功_N3pE，基于小分子的 QC 抑制剂也可以为早期 AD 治疗提供潜在的治疗选择。