Synthesis and Biological Evaluation of Atorvastatin Derivatives as Novel HMG-CoA Reductase Inhibitors

Hyperlipidemia is a common cardiovascular disease characterized by elevated lipid level in association with disordered lipoproteins metabolism. Atorvastatin, an HMG-CoA reductase inhibitor, has been developed as an antihyperlipidaemic agent and proved to exhibit antioxidant activity against lipid peroxidation. The two hydroxyl metabolites of atorvastatin, Ortho-hydroxy-atorvastatin and para-hydroxy-atorvastatin, are equipotent to their parent compound. Anethol trithione is a kind of liver protecting agent used to treat the hepatobiliary disease-related symptoms. Desmethyl anethol trithione, the degradation product of anethol trithione, keeps the related activity of anethol trithione and it is suitable for developing novel prodrugs. In this letter, a series of atorvastatin derivatives was designed as lipid regulators based on the structures of para-hydroxy-atorvastatin and desmethyl anethol trithione. Preliminary biological evaluation suggested compound 11a presented promising antihyperlipidemic, antioxidant activity and plasma stability. Keywords: Hyperlipidemia, Atorvastatin derivatives, Anethol trithione, Antihyperlipidaemic activity, Antioxidant activity, Plasma stability.