Approaches for the design of novel anti-atherogenic compounds.

Abstract

Atherosclerosis, a chronic disease related to the vascular system, is the most common cause of morbidity and mortality in Western society. Epidemiological studies have established that the serum cholesterol/triglyceride level is one of the major causative factors for its occurrence. At present, patients with persistent high levels of serum cholesterol and/or triglyceride are therapeutically treated with various types of drugs. Frequently applied drugs are inhibitors of a rate-limiting enzyme in the cholesterol synthesis pathway, i.e., 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, or bile acid sequestrants (fibrates). These drugs lead to an enhanced expression level of low-density lipoprotein (LDL) receptors, thereby stimulating the catabolism of LDL, the main carrier of cholesterol in human blood. Despite the general therapeutic efficacy of these drugs, a significant number of patients, including those suffering from familial hypercholesterolemia and dysbetalipoproteinemia, do not respond sufficiently to treatment with these drugs. In addition, HMG-CoA reductase inhibitors may induce unwanted side effects, since they only interfere with cholesterol synthesis but also lower the synthesis of other physiologically active isoprenoids. These considerations have prompted efforts to explore new frontiers in anti-atherosclerotic theraphy in order to expand the therapeutic scope for treating hyperlipidemia and hypercholesterolemia.