Department of Pharmaceutical Chemistry, School of Pharmacy, Aristotle University of Thessaloniki, 54124, Greece.
Dipartimento di Scienze Biomediche Sperimentali e Cliniche, Sezione di Scienze Biochimiche, Università degli Studi di Firenze, Viale Morgagni 50, 50134, Firenze, Italy.
Eur J Med Chem. 2025 Jan 5;281:117035. doi: 10.1016/j.ejmech.2024.117035. Epub 2024 Nov 8.
Diabetes mellitus is one of the most frequent metabolic diseases associated with hyperglycemia. Although antidiabetic drugs reduce hyperglycemia, diabetic patients suffer from abnormal fluctuations in blood glucose levels leading to the onset of long-term complications. Aldose reductase inhibitors are considered a promising strategy for regulating the occurrence of diabetic-specific comorbidities. So far, epalrestat is the only drug being approved in Asian countries. In this paper, we ground our research in discovering novel epalrestat analogs that prevent chronic complications and normalize hyperglycemia. Herein, we describe the rational design and synthesis of four novel 4-thiazolidinone acetic acid derivatives (AK-1-4) being evaluated for their efficacy against aldose reductase from rat lenses and their specificity over the homologous enzyme from rat kidneys. AK-1-4 were also tested against human recombinant protein tyrosine phosphatase 1B as a key target in insulin sensitization and towards the closely related T-cell-derived enzyme. Docking analyses suggested possible binding modes on examined targets. The promising inhibitory profile of AK-4 sparked our interest in exploring its effect on the insulin-receptor signaling pathway and its ability to stimulate glucose uptake under ex vivo conditions. We further investigated the ability of AK-4 to target mitochondria acting as an uncoupling agent and impairing mitochondrial membrane potential. Herein, we report for the first time a new glucose-lowering agent (AK-4) that can combine alleviation for chronic diabetic complications without off-target adverse effects and antihyperglycemic efficacy through controlled mitochondrial uncoupling activity. Pharmacokinetic and toxicity studies in silico revealed optimal properties of AK-4 for oral administration without potential side effects.
糖尿病是与高血糖相关的最常见代谢疾病之一。尽管抗糖尿病药物可降低高血糖，但糖尿病患者仍会出现血糖水平异常波动，从而导致长期并发症的发生。醛糖还原酶抑制剂被认为是调节糖尿病特异性合并症发生的一种有前途的策略。到目前为止，依帕司他是唯一在亚洲国家获得批准的药物。在本文中，我们基于发现可预防慢性并发症并使高血糖正常化的新型依帕司他类似物开展了研究。在此，我们描述了四种新型 4-噻唑烷酮乙酸衍生物（AK-1-4）的合理设计和合成，这些衍生物正在评估其对大鼠晶状体醛糖还原酶的功效及其对大鼠肾脏同源酶的特异性。还测试了 AK-1-4 对人重组蛋白酪氨酸磷酸酶 1B 的作用，因为该酶是胰岛素敏化的关键靶点，也是与 T 细胞衍生的酶密切相关的靶点。对接分析表明，在所研究的靶标上可能存在结合模式。AK-4 有希望的抑制谱引起了我们对其在胰岛素受体信号通路中的作用以及在体外条件下刺激葡萄糖摄取能力的兴趣。我们进一步研究了 AK-4 靶向线粒体作为解偶联剂并损害线粒体膜电位的能力。在此，我们首次报道了一种新型降糖剂（AK-4），它可以结合缓解慢性糖尿病并发症，而不会产生脱靶不良反应，并通过控制线粒体解偶联活性发挥降血糖作用。基于计算机的药代动力学和毒性研究表明，AK-4 具有口服给药的最佳特性，且没有潜在的副作用。
