Squalene synthase inhibitors

Abstract

Hypercholesterolaemia (defined as elevated levels [> 200 mg/dl] of plasma total cholesterol [TC]) is a significant risk factor for the development of atherosclerosis. The discovery and development of new hypocholesterolaemic agents has been a high priority for both pharmaceutical and academic researchers because of the devastating nature of the illness and the potentially huge patient population. Until recently, therapies for the treatment of hypercholesterolaemia suffered from a poor side-effect profile and lingering concerns over long-term toxicity. All of this changed with the introduction of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (HMGRIs), the most effective therapy to date in terms of lipid-lowering and side-effect profile. These compounds inhibit the enzyme, HMG CoA reductase, in the rate-limiting step of cholesterol biosynthesis and this results in significant decreases of plasma cholesterol at relatively low doses of HMGRI. The success of these agents has stimulated the search for other inhibitors of the multistep cholesterol biosynthetic pathway. Probably the most desirable enzyme to inhibit in this pathway is squalene synthase (SS). This is the only enzyme in the whole pathway that is solely committed to the synthesis of the sterol nucleus of cholesterol, and therefore inhibition would not affect the biosynthesis of other biologically important molecules. It is hoped that this would lead to an even better side-effect profile than the HMGRIs. Researchers have used substrate-based drug design, natural product screening and archival screening in their efforts to discover novel squalene synthase inhibitors. Whether the efficacy and safety of these agents in man will be superior to currently available therapies remains to be determined.