Lipitor, structure

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... 

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.)... 

For certain kinds of data sets, only the molecular structure makes sense, for example, databases of synthetic reactions. For a few others, only the salt form makes sense, for example, when you buy Lipitor or dispense it to a patient, what does 100 mg of Lipitor mean For the remaining, the molecular and salt forms are synonymous. 

An example of the value-added chain extending from commodities through fine chemicals to a pharmaceutical specialty is shown in Table 1.1. The product chosen is Pfizer s anticholesterol drug Lipitor (atorvastatin), the world s top-selling drug with sales of 12 billion in 2004. The value-added chain extends from a Ci molecule, methanol (left side of the table) all the way to a C33 molecule, atorvastatin. The structure of compound III in Table 1.1 is as follows ... 

Figure 6.1 Structures of atorvastatin (Lipitor ) and rosuvastatin (Crestor ).

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. 

Figure 2.128. (omega lipitor) The Xray crystal structure of Lipitor in its active conformation (green) overlaid by an Omega conformation which reproduces the active conformation to within 0.75 A rms... 

The food additive carnitine (25) is worthy of mention because it has a very close structural relationship to some beta blockers. It is also called vitamin BT. There are many potential routes to this compound, including an asymmetric hydrogenation method.234 236 The method is closely related to that used for Lipitor (Section 31.2.1). Reduction of 4-chloro-3-oxobutyrate provides the desired alcohol isomer. Ester hydrolysis and reaction with triethylamine affords 25. There are two other major approaches one relies on an asymmetric microbial oxidation (Scheme 31.22).237... 

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. 

Lipinski Rule of Five. 40. 55. 62 Lipitor. See Atorvastatin Lipophilicity.. 31. 65 Lipoprotcias clas.ses of. 657-658 metabolism of. 657-658 structure of. 657. 6S7f Lipotropins. 84.3-844 LiqucHed phenol. 221 Lisinopril. 645-646 Li.sier. Joseph. 217. 221 Lithane. See Lithium carbonate Lithium carbonate. 503 Lithium citrate. 503 Liver, drug metabolism in. 7—8. 66-68 LKTs. 820. 822 Local anesthetics. 676-694 alkaloids. 690... 

Apart from cases like these, we shall look for special methods to exercise 1,3-control. The importance of 1,3-control is immediately obvious from the structure of important cholesterollowering drugs like Lipitor (atorvastatin) 185. The. vvn-l,3-diol is a challenge but might be made from the amine 186 or the nitrile 187. 

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.

Figure 5.2 Structures of two HMG-CoA reductase inhibitors. Lipitor is actually the calcium salt of the compound depicted.

Fig. 3.6 Chemical structures of GMi ganglioside and statins. GMi ganglioside (a) atorvastatin (Lipitor) (b) and simvastatin (Zocor) (c)...

Fig. 7.1 Chemical structures of statins. Atorvastatin (Lipitor) (a) cerivastatin (Baycol) (b) ...

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

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. 

Fig. 1.1 An example based on the drug Lipitor of a simplified molecule-independent directory-based binary structural FP with its corresponding set of descriptors. The symbol X corresponds to any of the halogen atoms (F, Cl, Br, I)... 

FIGURE 1.1 The metabolic conversion of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) to mevalonate is a crucial step in the body s pathway for biosynthesizing cholesterol. An X-ray crystal structure ofthe active site in the HMG-CoA reductase enzyme that catalyzes the reaction is shown, along with a molecule ofatorvastatin (Lipitor) that is bound in the active site and stops the enzyme from functioning. With the enzyme thus inactivated, cholesterol biosynthesis is prevented. 

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