Statin Lipitor

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. 

Fig. 9.7 Chemical structures of statins. Lipitor (a) crestor (b) zocor (c) pravachof (d) and compactin (e)...

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). 

The recent years have seen the success of statins like Lipitor (atorvastatin) as hypolipidemic agents that help treating cardiovascular disease primarily by lowering low-density lipoproteins ( bad cholesterol ) levels. Another novel strategy is to tackle the same problem by elevating high-density lipoproteins (H D L or good cholesterol ) levels via inhibition of cholesteryl ester transfer protein (CETP). 

Baycol (cerivastatin, sold as Lipobay in Europe, Bayer) is a statin, a class of cholesterol-lower drugs. Statins are the most prescribed drugs in the United States, with more than 12 million people taking them, and more than 700,000 people in the United States taking cerivastatin. It received marketing approval on June 26, 1997 and was voluntarily removed from the market on August 8, 2001 because of its link to 100 deaths and several injuries from potentially the muscle disease rhabdomyolysis. The other statins — lovas-tatin (Mevacor Merck) pravastatin (Pravachol Bristol-Myers Squibb) simvastatin (Zocor Merck) fluvastatin (Lescol Novartis) atorvastatin (Lipitor Parke-Davis) rosuvastatin... 

Lipitor molecule at active site. Source. Istvan ES, Deisenhofer J. Structural mechanism for statin inhibition of HMG—CoA reductase, Science 292 1160 (2001). http //www.fda. gov/medwatch/SAFETY/2004/jul PI/Lipitor PI.pdf [accessed August 20, 2007]. Used with permission.)... 

The most important class of cholesterol-lowering agents is the statins. These include lovastatin (Mevacor), simvastatin (Zocor), pravastatin (Pravachol), and atorvastatin (Lipitor), among others. These molecules work, in modest part, by inhibiting biosynthesis of cholesterol and, in larger part, by increasing the rate at which cholesterol is eliminated by the body. Let s have a look at this in more detail. 

In Germany, the IQWIG has ruled that there are no grounds for the clinical superiority of Lipitor claimed by Pfizer to justify a higher price than for generic statins. ... 

Pfizer merges with Warner-Lambert and gains the rights to the highly successful anticholesterol statin drug Lipitor. 

The world s largest pharmaceutical company makes the anticholesterol statin drug Lipitor, the antidepressant Zoloft, and the erectile... 

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. 

This category includes atorvastatin (Lipitor), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin (Prava-chol), and simvastatin (Zocor) (Table 25-2). These drugs, known commonly as statins, are characterized by their ability to inhibit an enzyme known as 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase.96 This enzyme catalyzes one of the early steps of cholesterol synthesis, and drugs that inhibit HMG-CoA reductase decrease cholesterol produc-... 

Research on the pathway of cholesterol biosynthesis led to the development of a new class of drugs called statins. All statins, including atorvastatin (Lipitor, 2.22) and rosuvastatin (Crestor, 2.23), are inhibitors of the enzyme HMG-CoA reductase (Figure 2.6). Structurally, the acid side chain found on statin drugs closely resembles mevalonic acid (2.18). The side chain plays an important role in the binding of statins to HMG-CoA reductase. 

One class of antihyperlipidemic drugs is the statins. Statins interfere with the biosynthesis of cholesterol (A.103) and specifically inhibit the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (Scheme A.l). The statins that have been approved by the FDA include lovastatin (Mevacor, A.104), simvastatin (Zocor, A.105), pravastatin (Prava-chol, A.106), atorvastatin (Lipitor, A.107), rosuvastatin (Crestor, A.108), and fluvastatin (Lescol, A.109) (Figure A.29). All six compounds are drawn here to highlight the similarities between HMG-CoA (A.99) and mevalonic acid (A.100), and the top portion of the various statins. As a class, the statins have been extremely successful in terms of sales and effective in decreasing LDL cholesterol levels in the blood. 

Lactone 7 can serve as a versatile starting material for the synthesis of a range of HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, commonly referred to as statins, which includes Lipitor (8) and Crestor (9) compounds (Scheme 20.7). In a single transformation, the lactone ring can be opened and the chloride can be displaced by either cyanide or hydroxide to access advanced Lipitor or Crestor intermediates, respectively. 

Sometimes, the choice of comparator can backfire badly. Zocor Merck s Statin was run by Merck against Pfizer/Warner Lambert s Lipitor in another billion dollar study, and it was proven less effective. Merck made a huge favor to Pfizer that paid dearly but astutely to acquire Lipitor for its cardiovascular franchise. 

Mevacor), got FDA clearance in the United States in August 1987. Along with lovastatin, there are currently six statin drugs on the market the others are simvastatin (Zocor), pravastatin (Pravacol), fluvastatin (Lescol), atorvastatin (Lipitor), and rosuvastatin (Crestor). A seventh statin, cerivastatin (Baycol), was taken off the market following drug-related deaths. 

Statins are a class of cholesterol-lowering drugs that affect serum cholesterol levels by a variety of mechanisms. Examples include Lipitor, Zocor, Pravachol, Lescol, and Mevacor. Recent evidence... 

Figure 35.18 Synthetic statins. Atorvastatin (Lipitor) and rosuvastatin (Crestor) are completely synthetic drugs that inhibit HMG-CoA reductase.

E. The statin class of drugs—Lipitor (atorvastatin), Mevacor (lovas-tatin), and Zocor (simvastatin)—is used to treat hypercholesterolemia. This class of drugs lowers cholesterol levels by inhibiting the biosynthesis of cholesterol. Specifically, these drugs inhibit the enzyme P-hydroxy-P-methylglutaryl-CoA (HMG-CoA) reductase, which catalyzes the reaction that converts HMG-CoA to mevalonate. This is the rate-limiting step of cholesterol biosynthesis. 

You decide to treat a patient who has very high levels of serum cholesterol with the statin drug Lipitor (atorvastatin). You know that this drug acts in the metabolic pathway leading to the synthesis of cholesterol. The substrate for the enzyme inhibited by the statin drugs is which of the following ... 

Fig. 3. Chemical structures of HMG-CoA and several statin inhibitors of HMG-CoA reductase. Atorvastatin (Lipitor), simvastatin (Zocor), and pravastatin (Pravachol) are widely prescribed cholesterol-lowering drugs.

Atorvastatin Lipitor Caduet (in HMG-CoA reductase Reduction of LDL combination with inhibitor (statin) cholesterol levels by... 

Statins include atorvastatin calcium (Lipitor), cerivastatin (Baycol), fluvas-tatin (Lescol), lovastatin (Mevacor), pravastatin sodium (Pravachol), and simvastatin (Zocor). 

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