New Multifunctional Di-tert-butylphenoloctahydro(pyrido/benz)oxazine Derivatives with Antioxidant, Antihyperlipidemic, and Antidiabetic Action

• Published in: Journal of medicinal chemistry 2013-04, Vol.56 (8), p.3330-3338
• Main Authors: Ladopoulou, Eleni, Matralis, Alexios N, Kourounakis, Angeliki P
• Format: Article
• Language: English
• Subjects: Animals; Antioxidants - chemical synthesis; Antioxidants - pharmacology; Atherosclerosis - drug therapy; Blood Glucose - metabolism; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - complications; Diabetes Mellitus, Type 2 - drug therapy; Farnesyl-Diphosphate Farnesyltransferase - antagonists & inhibitors; Hyperlipidemias - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - pharmacology; Hypolipidemic Agents - chemical synthesis; Hypolipidemic Agents - pharmacology; Lipoproteins, LDL - metabolism; Male; Mice; Oxidative Stress - drug effects; Probucol - analogs & derivatives; Probucol - pharmacology; Rats
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm400101e

Oxidative stress, inflammation, and hyperlipidemia are common factors involved in the pathophysiology of atherosclerosis and type 2 diabetes. We have previously developed multifunctional antidyslipidemic derivatives with antioxidant and antiatherogenic properties. We now report the design, synthesis, and evaluation of two such novel derivatives that incorporate a structural moiety of the antidiabetic agent succinobucol. The new compounds exhibited a much improved in vitro antioxidant and squalene synthase inhibitory activity (at lower micromolar concentrations) as well as a significant antihyperlipidemic effect, reducing plasma total cholesterol, triglycerides, and MDA by 65–90%. Compound 2 also indicated a good anti-inflammatory activity, decreasing edema by 44%, while it was further evaluated for its antidiabetic activity using a type 2 diabetes experimental mouse model. After 7 weeks of administration, it produced a significant antihyperglycemic and antihyperlipidemic activity. In conclusion, rational drug design led to a compound combining improved antioxidant, antidyslipidemic, and antidiabetic action that may serve as a potential therapeutic strategy in metabolic syndrome disorders.