College of Pharmacy and Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea.
Medifron DBT, Seoul, 08502, Republic of Korea.
Eur J Med Chem. 2022 Aug 5;238:114444. doi: 10.1016/j.ejmech.2022.114444. Epub 2022 May 13.
The neurofibrillary tangles (NFTs) formed from hyperphosphorylation of tau protein are closely associated with Alzheimer's disease (AD). O-GlcNAcylation of tau can negatively regulate hyperphosphorylation and the O-GlcNAcase (OGA) catalyzes the removal of O-linked β-N-acetylglucosamine (O-GlcNAc) from tau protein. Therefore, preventing tau hyperphosphorylation by increasing the levels of tau O-GlcNAcylation via OGA inhibitors could be a promising approach. Based on Thiamet-G, a potent OGA inhibitor, and its binding mode to OGA, a novel OGA inhibitor scaffold bearing three parts was designed and hit compound 7j was successfully identified via extensive exploring. Further chemical optimization and diversification of the 7j structure resulted in compound 39 which possesses excellent OGA inhibition, no cytotoxicity, and has good pharmacokinetic properties. In acute AD model mice, 39 was more effective than Thiamet-G in inhibiting OGA activity attributable to its better blood-brain barrier permeability. In addition, 39 restored the cognitive function in mice and reduced amyloid-β (Aβ) concentrations to a greater extent than Thiamet-G. Molecular docking studies demonstrated that 39 was well associated with OGA through H-bonds and hydrophobic interaction. Together, these findings suggest that 39 was promising as a potent OGA inhibitor in the treatment of AD.
神经原纤维缠结（NFTs）是由微管相关蛋白 tau 的过度磷酸化形成的，与阿尔茨海默病（AD）密切相关。tau 的 O-GlcNAc 修饰可以负调控过度磷酸化，而 O-连接 N-乙酰氨基葡萄糖苷酶（OGA）催化从 tau 蛋白上去除 O-连接的β-N-乙酰氨基葡萄糖（O-GlcNAc）。因此，通过增加 tau O-GlcNAc 修饰水平来抑制 tau 过度磷酸化，通过 OGA 抑制剂增加 tau O-GlcNAc 修饰水平可能是一种很有前途的方法。基于强效的 OGA 抑制剂噻唑烷-4-酮（Thiamet-G）及其与 OGA 的结合模式，设计了一种具有三个部分的新型 OGA 抑制剂支架，并通过广泛探索成功鉴定出了先导化合物 7j。进一步对 7j 结构进行化学优化和多样化，得到了具有优异 OGA 抑制活性、无细胞毒性和良好药代动力学性质的化合物 39。在急性 AD 模型小鼠中，39 比 Thiamet-G 更有效地抑制 OGA 活性，这归因于其更好的血脑屏障通透性。此外，39 恢复了小鼠的认知功能，并比 Thiamet-G 更有效地降低了淀粉样蛋白-β（Aβ）浓度。分子对接研究表明，39 通过氢键和疏水相互作用与 OGA 结合良好。综上所述，这些发现表明 39 有望成为治疗 AD 的有效 OGA 抑制剂。
