Diabetes typically leads to the accumulation of advanced glycosylation end products (AGEs), which are capable of increasing the probability of vascular endothelial dysfunction. This is a crucial factor in microvascular and macrovascular pathology resulting in diabetic complications. Among the drugs for treating type 2 diabetes mellitus (T2DM), rosiglitazone (trade name Avandia�, GlaxoSmithKline) is used clinically to treat insulin resistance. However, RECORD trial shows that long-term use of this drug will increase the incidance of cardiovascular side effects, which has led to restriction order issued by the FDA. Given the beneficial effects of nitric oxide (NO) on endothelial function and of nitroxyl (HNO) as an anti-hypertensive and contractile agent, we are motivated to synthesize hybrid compounds of rosiglitazone bearing nitrate- and diazeniumdiolate-based NO or HNO donating moieties. A goal of this project is to determine whether these adducts can synergistically exert hypoglycemic and cardioprotective activity. The synthetic methodology and biological evaluation will be reported.

Nitric oxide and nitroxyl releasing rosiglitazone derivatives: Design, synthesis and biological evaluation

247th National Meeting (2014)

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