Atorvastatin structure

Atorvastatin, structure of, 105. 516 ATP (see Adenosine triphosphate) ATZ, see Anilinothiazolinone, 1031-1032 Aufbau principle. 6 Axial bonds (cyclohexane), 119 drawing, 120 Azide, amines from, 929 reduction of, 929 Azide synthesis, 929 Azo compound, 944 synthesis of, 944-945 uses of. 945... 

There are currently marketed four naturally derived statins (lovastatin, pravastatin, simvastatin, and rosuvas-tatin) and two synthetic statins (atorvastatin and fluvas-tatin). The structure of these statins is shown in Fig. 2. 

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... 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

The answer is d. (Hardman, pp 885-886. Katzung, pp 591-592.) Atorvastatin is a structural analogue of an intermediate formed from the action of HMG-CoA reductase. This could result in a modest decrease in plasma cholesterol. Hepatic cholesterol synthesis may decrease significantly however, nonhepatic tissues increase their rate of synthesis as a compensatory mechanism. The other and perhaps more important effect of the HMG-CoA inhibitors is to increase high-affinity LDL receptors. The plasma LDL is lowered by this action because of an increase in the catabolic rate of LDL and hepatic extraction of LDL precursors. 

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 ... 

These compounds are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A, Figure 35-3). Lovastatin, atorvastatin, fluvastatin, pravastatin, simvastatin, and rosuvastatin belong to this class. They are most effective in reducing LDL. Other effects include decreased oxidative stress and vascular inflammation with increased stability of atherosclerotic lesions. It has become standard practice to initiate reductase inhibitor therapy immediately after acute coronary syndromes, regardless of lipid levels. 

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

A wild-type DERA with less than 30% sequence identity to the E. coli enzyme led to a significant improvement over the E. coli wild-type DERA-based process originally described by Wong [15], The application of rational mutagenesis, based on the available crystal structure of the E. coli enzyme, expanded the range of suitable acceptor substrates for DERA to azido-substituted aldehydes, further facilitating access to, for example, the atorvastatin side chain [16]. 

These compounds are structural analogs of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A). (Figure 35-3). Lovastatin, atorvastatin, fluvastatin, pravastatin,simvastatin, and rosuvastatin... 

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. 

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... 

Figure 6-9 Chemical structures of atorvastatin and its metabolites derived from oxidative and conjugation pathways.

Lovastatin is a member of a class of drugs (atorvastatin and simvastatin are others in this class) called statins that are used to treat hypercholesterolemia. The statins act as competitive inhibitors of the enzyme HMG-CoA reductase. These molecules mimic the structure of the normal substrate of the enzyme (HMG-CoA) and act as transition state analogues. While the statins are bound to the enzyme, HMG-CoA cannot be converted to mevalonic acid, thus inhibiting the whole cholesterol biosynthetic process. Recent studies indicate that there may be important secondary effects of statin therapy because some of the medical benefits of statins are too rapid to be a result of decreasing atherosclerotic lesions. Statin therapy has been associated with reduced risks of dementia, Alzheimer disease, ischemic cerebral stroke, and other diseases that are not correlated with high cholesterol levels. Although this is still an active area of research, it appears that the pleiotropic effects of statins may be a result of a reduction in the synthesis of isoprenoid intermediates that are formed in the pathway of cholesterol biosynthesis. 

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.

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