The discovery that fibrates act as selective PPAR-a agonists has prompted the search for selective chemical entities as well as dual-acting PPAR agonists.56'90 Since PPARs are activated by naturally occurring polyunsaturated fatty acids, it is perhaps not surprising that fibrates would act as ligands for these receptors. PPARs are intimately involved in several of the early monocyte recruitment steps in atherosclerosis.90 PPAR-a agonists modulated chemokine (MCP-1) expression, whereas both PPAR-a and PPAR-g inhibited VCAM-1 expression in activated endothelial cells. PPAR-a agonists, and not PPAR-g, inhibited expression of the oxLDL receptor in endothelial cells. Both PPAR-a and PPAR-g agonists stimulated cholesterol efflux from foam cells, whereas dual PPAR-^S agonists promoted cholesterol accumulation in foam cells. PPAR-a agonists and dual PPAR-ag agonists are being targeted as potential new treatments for dyslipidemia and atherosclerosis.
Muraglitazar 43 (Figure 15), a dual PPAR-ag agonist, is the most advanced of these and is awaiting regulatory approval. In clinical trials, oral treatment of diabetic patients with daily doses of either 2.5 or 5 mg of muraglitazar as monotherapy lowered plasma glucose and TG levels (18-27%) dose-dependently and also increased plasma HDLc levels by 10-16%. Serum LDLc levels were modestly reduced by 3-5%.91
Was this article helpful?