Probucol is a traditional anti-hyperlipidemic agent harboring marked antioxidant activity. While probucol is highly hydrophobic, its succinic acid ester, succinobucol, was reported as a water-soluble derivative and was in clinical trials. Succinobucol was shown to be more potent in lipid-lowering, anti-inflammatory and anti-atherogenic effects than probucol in animal models. In addition, succinobucol reduced HbA1c in diabetic patients. Although the clinical trials finally ended in failure, it appears a promising strategy for drug discovery to modulate water-solubility of established active compounds. We have reported chemical modification of lipophilic agents with branched oligo-glycerol as a suitable approach to intensify hydrophilicity. Thus we synthesized highly hydrophilic derivative of probucol, Probucol-(glutaric branched-triglycerol)2 (ProBGL2) and evaluated its effects on glucose and lipid metabolism in high fat diet (HFD)-fed mice.Design and Method:
1 g/kg/day of probucol or ProBGL2 were orally administered to HFD-fed male ddY mice for a week, and then ipGTT was performed. Plasma insulin and lipid parameters were also determined. Furthermore, TBARS assay was performed to investigate antioxidant activities of probucol or ProBGL2.Results:
While body weight and food intake were not affected, glucose tolerance was improved in probucol and ProBGL2 groups. Fasting plasma insulin levels and HOMA-IR in the both groups were 70% decreased, suggesting increase in insulin sensitivity. However, ProBGL2 did not change plasma total cholesterol concentration though probucol lowered it. Furthermore, TBARS assay revealed ProBGL2 did not possess antioxidant activities in contrast to probucol. Plasma TG and NEFA levels were not altered. Interestingly, heart weight was decreased in probucol and ProBGL2 groups.Conclusions:
Our data show that probucol and its hydrophilic derivative, ProBGL2 ameliorate glucose tolerance, insulin resistance and cardiac hypertrophy in HFD-fed mice and those are independent of the canonical potency of probucol such as lipid-lowering or antioxidant activities. ProBGL2 should be a novel potent anti-diabetic agent.