Synthesis and Biological Evaluation of Gem-Difluoro- methylenated Statin Derivatives as Highly Potent HMG-CoA Reductase Inhibitors

HMG-CoA reductase inhibitors were widely used as lipid-lowing agents through effectively blocking the rate-limiting step of cholesterol biosynthesis. 8 analogs of Rosuvastatin were firstly prepared with different distance andfunctional group between the O5-hydroxyl group and terminal COOH group in the hydrophilic side-chain. In pri-mary and secondary screening of the inhibitory activities against human HMG-CoA reductase, gem-difluorometh-ylenated derivatives exhibited more than 50% inhibition rate. Then 4 compounds with gem-difluoro group werefurther synthesized and evaluated in vitro, three compounds among them exhibited low single digital nmol/L ICs0values against HMG-CoA reductase. Molecular docking also well explained the observed special contribution of thegem-difluoro group.