School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
J Med Chem. 2024 Jun 13;67(11):8836-8861. doi: 10.1021/acs.jmedchem.4c00159. Epub 2024 Jun 3.
More than 55 million individuals are suffering from Alzheimer's disease (AD), while the effective therapeutic strategies remain elusive. Our previous study identified a lysosome-enhancing lead compound with a tetrahydroisoquinoline scaffold through a novel dopamine transporter-cyclin-dependent kinase 9-transcription factor EB (DAT-CDK9-TFEB) regulation mechanism to promote TFEB activation and lysosome biogenesis. Here, we launched a comprehensive structure-activity relationship study for , and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds and exhibited more favorable TFEB activation and lysosome biogenesis capabilities, good safety profiles, and excellent pharmacokinetic profiles with high brain penetration. Further investigations demonstrated that both compounds significantly enhance the clearance of Aβ aggregates and ameliorate the impairment of learning, memory, and cognition in APP/PS1 mice. Overall, these results indicated that compounds and are promising preclinical drug candidates for the treatment of AD.
超过 5500 万人患有阿尔茨海默病（AD），而有效的治疗策略仍难以捉摸。我们之前的研究通过一种新的多巴胺转运体-细胞周期蛋白依赖性激酶 9-转录因子 EB（DAT-CDK9-TFEB）调控机制，发现了一种具有四氢异喹啉骨架的溶酶体增强先导化合物，以促进 TFEB 激活和溶酶体发生。在这里，我们对 进行了全面的构效关系研究，并设计和合成了 47 个新的衍生物，其中一些化合物表现出显著的溶酶体增强活性。值得注意的是，化合物 和 表现出更好的 TFEB 激活和溶酶体发生能力、良好的安全性特征和优异的药代动力学特征，具有较高的脑穿透性。进一步的研究表明，这两种化合物都能显著增强 Aβ 聚集体的清除，并改善 APP/PS1 小鼠的学习、记忆和认知损伤。总的来说，这些结果表明化合物 和 是治疗 AD 的有前途的临床前药物候选物。
