Vikramadithyan R K, Chakrabarti R, Misra P, Premkumar M, Kumar S K, Rao C S, Ghosh A, Reddy K N, Uma C, Rajagopalan R
Preclinical Biology, Dr. Reddy's Research Foundation, Hyderabad, India.
Metabolism. 2000 Nov;49(11):1417-23. doi: 10.1053/meta.2000.17734.
The euglycemic and hypolipidemic activities of PAT5A, a novel pyridine analog of thiazolidinedione, have been evaluated in different animal models. Administration of PAT5A to db/db mice resulted in dose-dependent decreases in plasma glucose, triglyceride, and insulin levels, and an improved glucose tolerance. The glucose-lowering activity of PAT5A was better than that of troglitazone and comparable to that of rosiglitazone. In addition, PAT5A showed better lipid-lowering activity than troglitazone or rosiglitazone. A similar profile was seen in ob/ob mice. In high-fat-fed Sprague Dawley rats, PAT5A treatment reduced plasma triglyceride and total cholesterol levels. An in vitro peroxisome proliferator activated receptor gamma (PPARgamma) transactivation assay in HEK-293 cells showed poor transactivation for PAT5A compared with rosiglitazone. PAT5A did not show any PPARalpha- or PPARdelta-activating properties. Ex vivo study in db/db mice treated with PAT5A showed decreased activity of liver glucose 6-phosphatase, a key enzyme in gluconeogenesis. A 28-day probe toxicity study in Wistar rats did not show any treatment-related alterations in hematologic and biochemical parameters, nor any macroscopic and microscopic changes in the vital organs, whereas rosiglitazone treatment increased liver and heart weights. Our results indicate that PAT5A is a potent insulin sensitizer and hypolipidemic compound with a weak PPARgamma activation potential. Both in vivo and in vitro results suggest that PAT5A improves glucose kinetics and lipid levels through mechanisms not related to PPAR activation.
噻唑烷二酮新型吡啶类似物PAT5A的正常血糖和降血脂活性已在不同动物模型中进行了评估。给db/db小鼠施用PAT5A导致血浆葡萄糖、甘油三酯和胰岛素水平呈剂量依赖性下降，且葡萄糖耐量得到改善。PAT5A的降糖活性优于曲格列酮，与罗格列酮相当。此外，PAT5A的降脂活性优于曲格列酮或罗格列酮。在ob/ob小鼠中也观察到了类似的情况。在高脂喂养的Sprague Dawley大鼠中，PAT5A治疗降低了血浆甘油三酯和总胆固醇水平。在HEK-293细胞中进行的体外过氧化物酶体增殖物激活受体γ（PPARγ）反式激活试验表明，与罗格列酮相比，PAT5A的反式激活能力较差。PAT5A未表现出任何PPARα或PPARδ激活特性。对用PAT5A治疗的db/db小鼠进行的体外研究表明，肝脏葡萄糖6-磷酸酶（糖异生中的关键酶）的活性降低。在Wistar大鼠中进行的为期28天的探针毒性研究未显示血液学和生化参数有任何与治疗相关的改变，重要器官也未出现任何宏观和微观变化，而罗格列酮治疗则增加了肝脏和心脏重量。我们的结果表明，PAT5A是一种具有弱PPARγ激活潜力的强效胰岛素增敏剂和降血脂化合物。体内和体外结果均表明，PAT5A通过与PPAR激活无关的机制改善葡萄糖动力学和脂质水平。
