2. Academic Validation
  3. Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease

Discovery and Optimization of Tetrahydroisoquinoline Derivatives To Enhance Lysosome Biogenesis as Preclinical Candidates for the Treatment of Alzheimer's Disease

  • J Med Chem. 2024 Jun 13;67(11):8836-8861. doi: 10.1021/acs.jmedchem.4c00159.
Jianhui Zhou 1 2,  Ning Wang 3,  Mengxue Wang 1 2 4,  Yuting Hu 1 2 4,  Zhenwei Zhang 2 4 5,  Zhiyong Gu 4 6 5,  Jing Wang 1 2 4,  Haowen Shou 2 4,  Xi Cheng 4 6 5,  Hong Liu 1 2 4 6 5,  Yang Li 3,  Yu Zhou 1 2 4 5
Affiliations

Affiliations

  • 1 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 2 Drug Discovery & Development Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 Department of Pharmacology, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, School of Basic Medical Science, Fudan University, Shanghai 200032, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
PMID: 38830007 DOI: 10.1021/acs.jmedchem.4c00159
Abstract

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 LH2-051 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 LH2-051, and 47 new derivatives were designed and synthesized, in which several compounds exhibited remarkable lysosome-enhancing activities. Notably, compounds 37 and 45 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 37 and 45 are promising preclinical drug candidates for the treatment of AD.

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