Cholesterol-reducing drugs Lipitor

Ethyl 4-chloro-3-hydroxybutyrate (EHCB) is an important intermediate in the production of l-camitine and the cholesterol-lowering Pfizer drug Lipitor (see Chapter 31). The ruthenium catalyst, [Ru(p-cymene)I((S)-TMBTP)]+E, has been reported to reduce ethyl 3-chlorobutyrate in 97% ee with S/C ratios of 20,000 (Scheme 12.48).87,157 This chemistry has been reported at scales >100 kg.87... 

The current therapy leaders are the anti-ulcerants such as Omeprazole (Prilosec ) or Lansoprazole (Prevacid ), which accounted for US 19.5 billion in 2001, thus claiming a market share of 6%. The anti-ulcerants are closely followed by the cholesterol reducers, e.g., Atorvastatin (lipitor ) and Simvastatin (Zocor ), totaling US 18.9 billion, the antidepressants (US 15.9 billion), and the NSAIDs (nonsteroidal anti-inflammatory drugs US 10.9 billion). Calcium antagonists, antipsychotics, oral antidiabetics, ACE inhibitors, cephalosporins, and antihistamines complete the list of the best-selling therapy classes, with sales between US 9.9 and 6.7 billion. It is interesting to note that four classes grew more than 20% in 2001, namely the cholesterol reducers (22%), the antipsychotics (30%), the oral antidiabetics (30%), and the antihistamines (22%) [4],... 

Among the synthetic drugs commercialized in more than 100 different countries and containing a heterocyclic core are Atorvastatin (Lipitor , (1)) [2], and Azoxystrobin (Amistar , (2)) [3] considered as a blockbuster blood cholesterol reducer preventing the cardiovascular diseases and a broad-spectrum fxmgicide, respectively (Figure 1). 

Isis, in collaboration with Genzyme, is developing a cholesterol-lowering drug, mipomersen, which is a secrmd generation 2 -G-(2-methoxy) ethyl-modified ribose ON. Unlike conventional therapies, mipomersen acts directly on apoUpoprotein BlOO, instead of inhibiting HMG-CoA reductase (as does Lipitor). Recent data showed that the drug is able to dramatically reduce low density lipoprotein (LDL) levels but also caused an unexpected increase in liver enzyme levels above the... 

Several drugs are now available to reduce the level of cholesterol in the bloodstream. These compounds act by blocking the biosynthesis of cholesterol at its very early stages. Two examples include atorvastatin (Lipitor) and simvastatin (Zocor), whose structures appear in Figure 29.12. 

Compactin and lovastatin are natural statins used clinically under the trade names Zocor and Mevacor . Atorvastatin (Lipitor) , a synthetic statin, is now the most popular statin. Lipitor has greater potency and a longer half-life than natural statins have, because its metabolites are as active as the parent drug in reducing cholesterol levels. Therefore, smaller doses of the drug may be administered. The required dose is reduced further because Lipitor is marketed as a single enantiomer. In addition, it is more lipophilic than compactin and lovastatin, so it has a greater tendency to remain in the endoplasmic reticulum of the liver cells, where it is needed. 

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. 

Green Biocatalysts for Production of Atorvastatin Codexis, Inc. has developed an enzyme-based process that has greatly improved the yield, efficiency, and safety record for manufacture of atorvastatin, the key building block for Lipitor , one of the world s best-selling drugs, that lowers cholesterol by blocking its synthesis in the liver. The new enzymatic process is dramatically faster and more efficient than previous methods, and also reduces cyanide-related waste, the use of solvents, and the need for purification equipment. 

Atorvastatin is one of a widely prescribed class of drugs called statins, which reduce a person s risk of coronary heart disease by lowering the level of cholesterol in their blood. Taken together, the statins—atorvastatin (Lipitor), simvastatin (Zocor), rosuvastatin (Crestor), pravastatin (Pravachol), lovastatin (Mevacor), and several others—are the most widely prescribed drugs in the world, with an estimated 14.6 billion in annual sales. 

We saw in Section 3.15 that statins (Lipitor, Zocor, Mevacor) lower serum cholesterol levels. These drugs are competitive inhibitors for the enzyme that reduces hydroxymethylglutaryl-CoA to mevalonic acid (page 1197). Recall that a competitive inhibitor competes with the substrate for binding at the enzyme s active site (Section 24.7). Decreasing the concentration of mevalonic acid decreases the concentration of isopentenyl pyrophosphate, so the synthesis of aU terpenes, including cholesterol, is decreased. As a consequence of diminished cholesterol synthesis, the liver forms more LDL receptors— the receptors that help clear LDL from the bloodstream. Recall that LDL (low-density lipoprotein) is the so-caUed bad cholesto-ol (Section 3.15). 

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