Lipitor action

Most of us are familiar with the effects of cholesterol. Exhibit 1.3 provides an explanation of how cholesterol is formed and the mechanism of action for Lipitor and Zocor in lowering the sterol. 

In another development, the statin side chain en route to Atorvastatin (Lipitor , Pfizer) is synthesized via the key intermediate alkyl 3-hydroxy-4-cyanobutyrate (Figure 13.17). Instead of the currently practiced six-step route, a much more concise three-step route starts from epichlorohydrin via Cl chain length enhancement by both nucleophilic substitution of chloride and nucleophilic ring opening of the epoxide with cyanide to yield symmetric dicyanoisopropanol. Nitrilase action desymmetrizes the dinitrile intermediate with the creation of a chiral center in C3 to yield (R)-3-hydroxy-4-cyanobutyrate, which is esterified to the key intermediate ethyl (R)-3-hydroxy-4-cyanobutyrate. 

Lipitor (l)2 is a cholesterol-lowering agent whose mode of action is as an HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor. It has been marketed by Pfizer and is sold as the calcium salt. 

Background It is well known that hypercholesterolemia is a major risk factor in the progression of atherosclerosis, the major cause of cardiovascular diseases. Statins are widely used to treat hypercholesterolemia. The mechanism of action of these drugs is to reduce the endogenous production of cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase. Atorvastatin (ATV, Lipitor) is one of the top-selling prescribed oral medications. The only known adverse effect is skeletal muscle toxicity (myopathy) that may be related to the formation of the lactone of the acidic side chain on the molecule. 

For example, the chapter-opening photograph shows a molecular model of atorvastatin, better known as Lipitor . In the body, Lipitor inhibits the action of a key enzyme, called HMG-CoA reductase (we will discuss enzymes in Section 14.7). HMG-CoA reductase is a large complex biomolecule that is critical in the biochemical sequence that synthesizes cholesterol in the liver, and inhibition of its action leads to reduced cholesterol production. The molecules of Lipitor have two properties that lead to their pharmaceutical effectiveness ... 

Atorvastatin (Lipitor) is used to decrease patient serum cholesterol levels. It works by inhibiting an enzyme called HMG-CoA reductase. See "Connections to Biological Chemistry"in Section 10.2 for more information about the action of atorvastatin. In one synthesis of atorvastatin that produces the desired single enantiomer of the final product, the following reagents are used. Draw the structures of synthetic intermediates A and B. 

---