Novel Dual-ACTING PEROXISOME Proliferator-Activated Receptor Alpha and Gamma Agonists.

Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors, and play a central role in insulin sensitivity, lipid metabolism, and inflammation. PPAR -gamma appears to improve glycaemic control by increasing peripheral insulin sensitivity and reducing hepatic glucose production, thereby helping to preserve beta-cell function. However, they have modest beneficial effects on lipid parameters. It has been observed that fibrate drugs which activate PPAR-alpha, produce significant improvements in dyslipidaemia and decrease atherosclerotic lesions, but do not affect glycaemia. Theoretically, a compound targeting both the a and. PPARs simultaneously, might combine the benefits of thiazolidinediones (TZDs) and fibrates. Hence, there is a resurgence of interest in the development of new antidiabetic drugs that combine the insulin-sensitizing effects of PPAR. activation with the additional lipid-modifying activity of the other PPAR subtypes. Muraglitazar, Tesaglitazar, Ragaglitazar, Isohumulone, Farglitazar, and Naveglitazar are on the deck in late-stage clinical trials, and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. The ongoing basic studies have elucidated the cardio protective role of PPAR delta. Therefore, further studies are on the track to develop PPA beta/delta and PPAR gamma/delta dual agonists and PPAR alpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications.