2. Academic Validation
  3. Structure Optimization of Natural Product Catalpol to Obtain Novel and Potent Analogs against Heart Failure

Structure Optimization of Natural Product Catalpol to Obtain Novel and Potent Analogs against Heart Failure

  • J Med Chem. 2025 Feb 27;68(4):4540-4560. doi: 10.1021/acs.jmedchem.4c02591.
Hanfang Liu 1,  Xiaobo Guo 1,  Jin Yang 1,  Conglong Xia 2,  Yue Yao 1,  Xiao Li 1,  Xiaoyang Liu 1,  Junqi Yang 1,  Xiaokang Li 1,  Yixiang Xu 1,  Jian Li 1 3 4,  Manjiong Wang 1
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioreactor Engineering, Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism, Frontiers Science Center for Materiobiology and Dynamic Chemistry, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
  • 2 College of Pharmacy, Dali University, Dali 671000, China.
  • 3 Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832003, China.
  • 4 Key Laboratory of Tropical Biological Resources of Ministry of Education, College of Pharmacy, Hainan University, Haikou 570228, China.
PMID: 39925333 DOI: 10.1021/acs.jmedchem.4c02591
Abstract

Heart failure (HF) is a major global health threat, characterized by high morbidity and mortality. Targeting cardiac hypertrophy has been identified as a potential therapy for HF, with current treatments showing limited efficacy. Our research aims to address this limitation by exploring new structural classes of therapeutic agents. Starting from the natural product catalpol, we designed a series of novel catalpol analogs to break through the structural limitations of natural analogs, improve the anti-HF efficacy and metabolic properties. Among these, compound JZ19 exhibited remarkable efficacy in both myocardial cell injury assays and in an isoproterenol-induced murine HF model, outperforming catalpol. Our findings indicate that JZ19 potently reversed cardiac function by modulating the PI3K-AKT-GSK3β pathway, a key regulator of hypertrophy and Apoptosis. Moreover, JZ19 showed favorable pharmacokinetic properties and safety. Overall, our results provide direct pharmacologic evidence supporting the further development of JZ19 as novel HF therapeutics by inhibiting cardiac hypertrophy and Apoptosis.

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