Steroid Hormones Cholesterol as a Biosynthetic Precursor

Since cholesterol is the biosynthetic precursor of all the steroid hormones, a consideration of cholesterol biochemistry is central to medicinal chemistry and rational dmg design as applied to steroids. Although cholesterol plays a role in a variety of processes, its participation in gallstones and atherosclerosis are probably its two most important aspects. 

Enconragingly, there is increasing, robust scientific evidence that atherosclerosis can be arrested and even decreased by pharmacologic approaches. However, the evaln-ation of drug therapy for this condition is complicated by the fact that the regulation of cholesterol metabolism alone does not necessarily have a beneficial effect on atherosclerosis. 

According to our present knowledge, there are several ways to treat disorders (referred to as hypercholesterolemias or hyperlipoproteinemias) that enhance cholesterol-containing atheroma formation. The class of compounds referred to as statins dominates the treatment of these disorders. 

In addition to treatment with the statins, hypercholesterolemia is sometimes treated with the use of nonabsorbable anion-exchange resins like cholestyramine (5.13) and colestipol, which sequester bile acid in the intestine, excrete them, and thus increase their synthesis in the liver by a feedback mechanism. Increased bile acid synthesis increases cholesterol metabolism and also decreases LDL concentrations. Unfortunately, these resins interfere with the absorption of other fats and fat-soluble vitamins (A, D, E, and K). They 

Nicotinic acid (5.18), and related derivatives such as pyridylcarbinol (5.19), xanthinol nicotinate (5.20), acipimox (5.21), given in large doses, influence the lipoprotein ratio, decreasing the concentrations of very low and low-density lipoprotein, but have no effect on HDL-cholesterol complexes. Acipimox (5.21) is a new pyrazine derivative that is 20 times more active than nicotinic acid. When first administered, the use of these agents is associated with flushing and hypotension. 

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