Synthesis and lipid-lowering evaluation of 3-methyl-1H-purine-2,6-dione derivatives as potent and orally available anti-obesity agents

摘要

Obesity accompanied with metabolic disorder is often complicated with a strong link of dyslipidemia and insulin resistance, whose indicator is the excess accumulation of triglycerides (TG) in cells. Consideration the idea of lipid-lowering and improving insulin resistance, 34 novel compounds by combination the xanthine scaffold with the chain of Rosiglitazone have been synthesized. Among them, several compounds showed efficiency on reducing TG in 3T3-L1 adipoctyes, and 11c exhibited the most optimal capacity in lipid-lowering and improving obese clinical symptoms in DIO mice. Furthermore, the hydrochloride of 11c (11c center dot HCl) showed excellent bioavailability, 58.94%, over 2 folds than that (28.03%) of 11c, and the anti-obesity effect of 11c center dot HCl at 50 mg/kg dose was better than that of Metjormin at 150 mg/kg dose in DIO mice, almost reversed HFD to a normal level. Thus, 11c center dot HCl might be a potent and orally available anti-obesity agent via alleviating the obese clinical symptoms, body fat, improving serum parameters and insulin resistance and TG clearance in liver. (c) 2014 Published by Elsevier Masson SAS.