Chemistory of Fibrates

Since the description of the synthetic chemical clofibrate in 1962, various derivatives of fibrates with a diversity of chemical structures have been developed. Several of these are used clinically to treat dyslipidemia because they are generally effective in lowering elevated plasma triglycerides and cholesterol. Studies suggest that several biochemical mechanisms underlie fibrate-mediated modulation of lipoprotein and related metabolites. These mechanisms are: 1) induced lipoprotein lipolysis; 2) induced hepatic fatty acid uptake and reduced hepatic triglyceride formation; 3) amplified removal of low density lipoprotein (LDL) particles; 4) reduced neutral lipid (cholesteryl ester and triglyceride) exchange between very low density lipoprotein (VLDL) and high density lipoprotein (HDL) resulting from decreased plasma levels of triglyceride-rich lipoprotein (TRL); and 5) increased HDL production and stimulation of reverse cholesterol transport. Recent studies of structure-based inhibitor design strategy revealed that an independent enzyme, aldose reductase (AR), is a target of fibrate activity, an additional biochemical mechanism. AR has been implicated as a major player in the development of diabetes and diabetic complications because of its ability to catalyze the conversion of glucose to sorbitol. This article discusses various targets of fibrate action, biochemical pathways and commonalities in potential molecular interactions.