Alzheimer's disease (AD) is one of the most common neurodegenerative causes of dementia, the pathology of which is still not much clear. It′s challenging to discover the disease modifying agents for the prevention and treatment of AD over the years. Emerging evidence has been accumulated to reveal the crucial role of up-regulated glutaminyl cyclase (QC) in the initiation of AD. In the current study, the QC inhibitory potency of a library consisting of 1621 FDA-approved compounds was assessed. A total of 54 hits, 3.33 % of the pool, exhibited QC inhibitory activities. The Ki of the top 5 compounds with the highest QC inhibitory activities were measured. Among these selected hits, compounds affecting neuronal signaling pathways and other mechanisms were recognized. Moreover, several polyphenol derivatives with QC inhibitory activities were also identified. Frameworks and subsets contained in these hits were analyzed. Taken together, our results may contribute to the discovery and development of novel QC inhibitors as potential anti-AD agents.

中文翻译：

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重新利用 FDA 批准的化合物以发现谷氨酰胺环化酶抑制剂作为抗阿尔茨海默病的药物

阿尔茨海默病 (AD) 是痴呆最常见的神经退行性疾病之一，其病理学仍不太清楚。多年来发现用于预防和治疗 AD 的疾病调节剂具有挑战性。已经积累了新的证据来揭示上调的谷氨酰胺酰环化酶 (QC) 在 AD 发病中的关键作用。在目前的研究中，评估了由 1621 种 FDA 批准的化合物组成的文库的 QC 抑制效力。总共 54 个命中，占池的 3.33%，表现出 QC 抑制活性。测量了具有最高 QC 抑制活性的前 5 个化合物的 Ki。在这些选定的命中，影响神经元信号通路和其他机制的化合物被识别。而且，还鉴定了几种具有 QC 抑制活性的多酚衍生物。分析了这些命中中包含的框架和子集。总之，我们的结果可能有助于发现和开发新的 QC 抑制剂作为潜在的抗 AD 剂。