Jie Caitlin V M L, Delparente Aro, Reichert Lisa, Albrecht Manuela, Atz Kenneth, Schneider Gisbert, Schibli Roger, Mu Linjing
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zürich, CH-8093, Zurich, Switzerland.
Chemistry. 2025 Apr;31(24):e202404517. doi: 10.1002/chem.202404517. Epub 2025 Feb 7.
ATP synthase dysregulation has been implicated in many diseases, including cancer and neurodegenerative diseases. Whilst ATP synthase-targeting compounds have been reported, most are large or polar compounds and lack appropriate properties for a CNS drug. We designed, synthesised, and evaluated a novel series of ATP synthase targeting compounds, resulting in a 1,3,4-oxadiazin-5-one scaffold with improved physiochemical properties. In vitro evaluation of our library led to the discovery of CJ1-34 as a partial ATP synthase inhibitor with a determined IC of 394 nM in isolated bovine mitochondria. Molecular docking experiments demonstrated that calculated docking scores aligned with the observed in vitro pharmacology and supports the F region of the ATP synthase as the potential binding site. Overall, this provides the foundation to further investigate CJ1-34 as a potential CNS drug for diseases where mitochondria are implicated, including Alzheimer's and Parkinson's disease.
ATP合酶失调与许多疾病有关，包括癌症和神经退行性疾病。虽然已经报道了靶向ATP合酶的化合物，但大多数是大分子或极性化合物，缺乏作为中枢神经系统药物的合适特性。我们设计、合成并评估了一系列新型的靶向ATP合酶的化合物，得到了一种具有改善物理化学性质的1,3,4-恶二嗪-5-酮支架。对我们的化合物库进行体外评估，发现CJ1-34是一种部分ATP合酶抑制剂，在分离的牛线粒体中测定的IC为394 nM。分子对接实验表明，计算出的对接分数与观察到的体外药理学结果一致，并支持ATP合酶的F区域作为潜在的结合位点。总体而言，这为进一步研究CJ1-34作为一种潜在的中枢神经系统药物用于涉及线粒体的疾病，包括阿尔茨海默病和帕金森病，提供了基础。
