In addition to high levels of serum cholesterol and cholesterol esters, a combination
of other molecular factors appears to be necessary for the development of atherosclero-
sis. Among these additional molecules, lipoproteinsare crucial. Lipoproteins are
macromolecular assemblies consisting of lipids (cholesterol, triglycerides) noncova-
lently bound with protein and, to a lesser extent, carbohydrate. These collections of
molecules have a spherical shape and consist of a nonpolar core surrounded by a mono-
layer of phospholipids whose polar groups are oriented out; within the phospholipid
monolayer are a small number of cholesterol molecules and proteins, called
apolipoproteins. Lipoprotein particles solubilize lipids, preventing insoluble aggregates
in the plasma and enabling cholesterol transport in the aqueous plasma. These solubi-
lized collections of cholesterol and other lipids can more readily penetrate damaged
arterial walls, thereby promoting atherosclerosis.
The various types of lipoproteins that carry cholesterol can be separated and cate-
gorized by ultracentrifugation. From a molecular viewpoint, the ratio of these various
serum lipoproteins is of major clinical importance. There are three main types of
lipoproteins: very low-density (VLDL), low-density (LDL), and high-density (HDL)
lipoproteins. VLDL is 60% triglyceride, 18% phospholipid, and 12% cholesterol; LDL
consists of 50% cholesterol and 10% triglycerides; HDL is 25% cholesterol and 50%
protein. The first two types (VLDL, LDL) seem to increase atherosclerosis, whereas
the high-density lipoproteins seem to decrease the incidence of atheroma formation.
High-density lipoproteins may even facilitate the removal of cholesterol from the
arterial wall. This is probably accomplished in two ways: by the increased esterifica-
tion of cholesterol, and by inhibition of the LDL–cholesterol complex uptake by the
cells of the arterial wall. Since atherosclerosis is a fundamental pathology, leading to
stroke and heart attack, manipulations of cholesterol and lipoproteins are important in
drug design.
According to our present knowledge, there are several ways to treat disorders
(referred to as hypercholesterolemiasorhyperlipoproteinemias) that enhance choles-
terol-containing atheroma formation. The class of compounds referred to as statins
dominates the treatment of these disorders.
The statins (lovastatin (5.7), simvastatin (5.8), pravastatin (5.9), fluvastatin (5.10),
cerivastatin (5.11), atorvastatin (5.12)) target liver biochemistry. As discussed above,
cholesterol is an essential constituent in human metabolism, and the liver obtains 60%
of its required cholesterol from de novosynthesis, starting with acetylcoenzyme-A.
A crucial step in this synthesis is the conversion of hydroxymethylglutaryl CoA (HMG
CoA) to mevalonic acid, a conversion catalyzed by the HMG CoA reductase enzyme.
The pharmacophore of these statin drugs resembles the substrate of this enzyme. In the
presence of statin-type drugs, liver cells increase the synthesis of LDL receptor proteins
and uptake and removal of LDL from the systemic circulation. The end result of this
effect is an overall reduction in harmful atherosclerosis-promoting lipids. Lovastatin
and simvastatin are lactones that undergo significant first-pass effect in the liver, being
hydrolyzed to bioactive metabolites; pravastatin and fluvastatin, on the other hand, are
organic acids that are administered in a bioactive form. A potentially dangerous side
effect of the statins is skeletal muscle damage, a risk that is augmented if the statin is
co-administered with a fibric acid analog. The action of statins is intensified if they are
co-administered with ion exchange resins.
318 MEDICINAL CHEMISTRY