Fibrate Acids and Esters for the Treatment of Hyperlipidemia (PPARα Activators)

The fibrates are a class of carboxylic acid derivatives that have been used in the treatment of hyperlipidemia. Structurally, the fibrates are derivatives of fibric acid, with the minor exception of gemfibrozil, which replaces the phenoxymoiety with a short alkyl chain. Clofibrate, developed by Imperial Chemical Industries (ICI), was the first fibrate. Currently, generic versions of four fibrates are available in various European countries: bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil. Jeff Thorp, a chemist at ICI, initiated a course of research which ultimately led to the discovery of the prototypical member of the fibrate class, ethyl-a-p-chlorophenoxyisobutyrate. The chapter reviews the synthesis of bezafibrate, ciprofibrate, fenofibrate, and gemfibrozil. The fibrates are comparatively low-potency activators of peroxisome proliferator-activated receptors-α (PPARα), a fact that is reflected in the typical doses required to exert the desired hypolipidemic effect. Within the class, the prototypical clofibric acid is the least potent PPARα activator.