University of St. Andrews, School of Biology, Medical and Biological Sciences Building, North Haugh, St. Andrews KY16 9TF, UK.
University Hospital, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
Molecules. 2019 Jul 29;24(15):2757. doi: 10.3390/molecules24152757.
It has long been established that mitochondrial dysfunction in Alzheimer's disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells.
长期以来，人们已经发现阿尔茨海默病（AD）患者中线粒体功能障碍可以通过改变代谢酶（如线粒体 17β-羟类固醇脱氢酶 10 型（17β-HSD10），也称为淀粉样蛋白结合醇脱氢酶（ABAD））来触发细胞代谢的病理变化。我们和其他人已经表明，戊唑醇和利鲁唑衍生物可以抑制 17β-HSD10，并且这种抑制是有益的，并且对 AD 的治疗具有治疗价值。在这里，我们评估了几种基于苯并噻唑基脲支架的新型系列，评估了抑制 17β-HSD10 所需的关键结构和活性关系。结果表明，这些化合物中最有前途的化合物对我们之前发表的抑制剂具有明显增强的效力，其中最有前途的化合物具有有利的特征，如低细胞毒性和在活细胞中的靶标结合。
