Potential role of nonstatin cholesterol lowering agents

""Although statins, 3b-hydroxy-3b-methylglutaryl coenzyme A. reductase (HMGR) inhibitors, have revolutionized the management. of cardiovascular diseases by lowering serum low density. lipoproteins, many patients suffer from their side effects.. Whether the statin side effects are related to their intrinsic toxicity. or to the decrease of HMGR main isoprenoid end products,. which are essential compounds for cell viability, is still. debated. In addition to HMGR, the key and rate limiting step. of cholesterol synthesis, many enzymes are involved in this. multi-step pathway whose inhibition could be taken into. account for a ‘‘nonstatin approach’’ in the management of. hypercholesterolemia. In particular, due to their unique position. downstream from HMGR, the inhibition of squalene synthase,. farnesyl diphosphate farnesyltransferase (FDFT1), squalene. epoxidase (SQLE), and oxidosqualene cyclase:lanosterol synthase. (OSC) should decrease plasma levels of cholesterol without. affecting ubiquinone, dolichol, and isoprenoid metabolism.. Thus, although FDFT1, SQLE and OSC are little studied, they. should be considered as perspective targets for the development. of novel drugs against hypercholesterolemia. Here, structure–. function relationships of FDFT1, SQLE, and OSC are reviewed. highlighting the advantages that the downstream inhibition of. HMGR could provide when compared to the statin-based. therapy.""