Cholesterol Lipitor

Again, Merck spent 91.2 million on DTC ads for Zocor in 2000, versus just 58.2 million that Pfizer spent on Lipitor, yet Lipitor led in sales—and this time, Merck had no excuses. It was Merck that had created the whole anticholesterol category in 1987 with Mevacor. But it lost cholesterol. Lipitor blew it away with a lower price and a more potent initial dose. While the higher dose might cause worse side effects, it sure made the drug look more effective in the marketing. 

Many valuable compounds are aromatic in part, including steroids such as estrone and well-known pharmaceuticals such as the cholesterol-lowering drug alorvastatin, marketed as Lipitor. Benzene itself has been found to cause bone marrow depression and a consequent lowered white blood ceil count on prolonged exposure. Benzene should therefore be handled cautiously if used as a laboratory solvent. 

The study concerns the desymmetrization of the prochiral dinitrile (16) with preferential formation of the (Ji)-17, which was known to be a chiral intermediate in the synthesis of the cholesterol-lowering therapeutic drug (18) (Lipitor, Sortis, Torvast, etc.) as shown in Scheme 2.3. 

The cholesterol-lowering drug atorvastatin, marketed as Lipitor, is an example where biocatalysis research has been applied extensively and is in industrial use. The enzyme 2-deoxyribose-5-phosphate aldolase (DERA) has been a target of directed evolution for the production of atorvastatin intermediates [8,9,71]. DeSantis and coworkers [8,9] used structure-based... 

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... 

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. 

An enzyme (see Section 2.6) called HMG-CoA reductase is involved in the biosynthesis of cholesterol. Drugs such as atorvastatin (Lipitor) and simvastatin (Zocor) are competitive inhibitors of HMG-CoA reductase. They inhibit cholesterol synthesis by increasing the number of LDL receptors to take up the LDL. 

Atorvastatin (Lipitor, Pfizer) and simvastatin (Zocor, Merck) HMG-coenzyme A inhibitors for the reduction of cholesterol level in blood (refer to Exhibit 1.3). 

This cholesterol formation reaction is catalyzed by the enzyme HMG-CoA reductase. One means to stop or reduce the production of cholesterol is to interfere with the supply of mevalonate. This is the function of Lipitor, which acts as an inhibitor of HMG-CoA reductase. 

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. 

Lipitor is currently one of the best selling drugs for lowering cholesterol. Searching in WDI for Lipitor produces the page shown in Figure 10.1 [46]. The preferred name is Atorvastatin Calcium . WDI has information about the pharmacology, indications, interactions, and so on, hyperlinked for keyword search. 

Fig. 10.6 Metabolic pathway between HMG-CoA reductase and cholesterol (altered by Lipitor).

Lipitor (Parke-Davis) Atorvastatin 48.8 High cholesterol... 

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-... 

Generic Name Atorvastatin Trade Name(s) Lipitor Dosage 10-80 mg once each day Primary Effect Decreases total cholesterol and plasma LDL-C may also decrease triglycerides and increase HDL-C somewhat... 

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. 

Atorvastin (Lipitor, 13.40) is a cholesterol-lowering drug that has been synthesized as a single enantiomer through use of a chiral auxiliary (Scheme 13.6).16 Ester 13.36 contains the auxiliary, a chiral alcohol. Deprotonation of the ester forms an enolate (13.37). The enolate then attacks an aldehyde. The asymmetry of the stereocenter on the auxiliary causes the reaction to favor stereoisomer 13.38 over 13.39. Several recrystallizations are required to obtain 13.38 in high enantiomeric excess. Cleavage of the auxiliary from 13.38 and further manipulations of the side-chain afford atorvastin. 

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. 

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... 

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