Inhibition of cholesterol synthesis

Efforts to find inhibitors of cholesterol synthesis, which might act as hypocholesterolemic agents, have been going on for over 30 yr. One difficulty with this approach is that we are dealing with an integral metabolite rather than a foreign substance. It is thought that the ideal place for inhibition of synthesis would be a water-soluble intermediate between hydroxymethylglutaryl coenzyme A (HMG CoA) and squalene. Several inhibitors of cholesterol synthesis that acted in later stages showed an increase of a new steroid in the blood that usually accumulated at the stage of inhibition. A few of these compounds have also been shown to be teratogenic for rats. Currently there is a new generation of inhibitors whose site of action is at HMG CoA reductase. Fortunately, at this writing no serious side effects have been reported.