Hypolipidemic activity in a series of new hybrids of orotic acid and 1,2,4-triazole

Abstract

Cardiovascular diseases associated with hyperlipidemia remain one of the leading causes of morbidity and mortality world-wide. Therefore, the search for new hypolipidemic agents with improved efficacy and safety profiles remains an important task of modern pharmacology. The aim of this study was to evaluate the hypolipidemic and antiatherosclerotic activity of sodium 5-(2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)-4-ethyl-4H-1,2,4-triazole-3-thiolate (KP-372), a new hybrid derivative of orotic acid and 1,2,4-triazole, in a rat model of alimentary hyperlipidemia. Hyperlipidemia was induced in male rats by dietary administration of 4% cholesterol, 0.12% 6-methyluracil, and 25% sunflower oil for 14 days. Four groups of 10 animals each were formed: KP-372-treated, atorvastatin-treated, placebo, and intact. In the placebo-treated rats, the serum lipid profile showed clear dyslipidem-ia, with cholesterol 1.84 ± 0.08 mmol/L, triglycerides 0.81 ± 0.03 mmol/L, low-density lipoproteins 0.52 ± 0.03 mmol/L, and very low-density lipoproteins 0.36 ± 0.06 mmol/L versus 1.29 ± 0.09, 0.44 ± 0.04, 0.40 ± 0.03, and 0.20 ± 0.02 mmol/L, respec-tively, in intact animals. Administration of KP-372 improved these indices to 1.49 ± 0.09 mmol/L for cholesterol, 0.53 ± 0.05 mmol/L for triglycerides, 0.39 ± 0.08 mmol/L for low-density lipoproteins, and 0.23 ± 0.02 mmol/L for very low-density lipopro-teins. In the atorvastatin group, the corresponding values were 1.50 ± 0.12, 0.44 ± 0.03, 0.52 ± 0.03, and 0.20 ± 0.02 mmol/L. Thus, KP-372 showed activity comparable to atorvastatin and a more favorable effect on low-density lipoproteins. Morphologi-cally, placebo-treated animals demonstrated the most severe hepatic lesions with vacuolar fatty degeneration, necrobiotic chang-es, vascular congestion, and cellular infiltration, whereas KP-372 treatment was associated with milder changes, mainly granular and ballooning degeneration. Molecular docking showed a higher predicted affinity of KP-372 for pancreatic lipase than for 3-hydroxy-3-methylglutaryl-coenzyme A reductase, with binding energies of –7.260 and –5.136 kcal/mol, respectively, supporting a mechanism more closely related to modulation of dietary lipid digestion and absorption than to a classical statin-like pathway. These findings indicate that KP-372 is a promising hypolipidemic agent.