Simvastatin, structure

Pravastatin (5) is another HMG-CoA reductase for the inhibition of cholesterol biosynthesis. It is closely related to lovastatin and simvastatin structurally (see Sections 3.2.9 and 3.2.2). It is produced by a two-step sequence ML-236B (6) is prepared by fermentation of Penicillium citrinum [13], then hydroxylated enzymatically to produce (5) [13-15]. 

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. 

Simvastatin, a conjugated alkene, can polymerise as a result of peroxyl radical addition. The peroxide-linked oligomers can be subsequently cleaved to produce epoxides, which in turn degrade to form ketones and alcohols [69]. Inclusion of vitamin E (a-tocopherol) into formulations was found to inhibit chain-oxidation of simvastatin, lovastatin and other structurally related statins. 

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. 

Inhibition by drugs The statin drugs, including simvastatin, lovastatin, and mevastatin, are structural analogs of HMG CoA, and are reversible, competitive inhibitors of HMG CoA reductase (Figure 18.7). They are used to decrease plasma cholesterol levels in patients with hypercholesterolemia.1... 

Structural similarity of HMG and simvastatin, a clinically useful cholesterol-lowering drug of the statin" family. 

Eckernas SA, Roos BE, Kvidal P, Eriksson LO, Block GA, Neafus RP, Haigh JR. The effects of simvastatin and pravastatin on objective and subjective measures of nocturnal sleep a comparison of two structurally different HMG CoA reductase inhibitors in patients with primary moderate hypercholesterolaemia. Br J Clin Pharmacol 1993 35(3) 284-9. 

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

The high-value HMG-CoA reductase inhibitor Simvastatin (8) is marketed by Merck under the name Zocor. The active ingredient is obtained from a fermentation approach. It is very similar in structure to lovastatin, which has fallen from the top-sellers list. Lovastatin (9) is also a cholesterol-reducing drug that is isolated from Aspergillus terreus.51-60 It is still obtained by fermentation,61 and with the current advances in molecular biology,62 64 chemical approaches are not able to compete in a cost-effective manner.65-67 The usage of lipases allows for the manipulation of the butyric acid sidechain to access other HMG-CoA reductase inhibitors such as simvastatin.68 A number of routes to various portions of lovastatin have been reported.69... 

As mentioned, fermentation is used to provide the core structure of simvastatin, and hydrolysis is used to remove the 2-methylbutyrate sidechain the dimethylbutyric acid sidechain is introduced by coupling (Scheme 31.6).70-73 Chemical methylation to form the quaternary dimethylated center in the sidechain has been achieved on synthetic intermediates.7475 The chemical approach has to differentiate two hydroxy groups, and this requires protection-deprotection steps.76-86... 

A4 Midazolam, Testosterone (strongly recommended to use at least two structurally unrelated substrates) Nifedipine, Felodipine, Cyclosporine, Terfenadine, Erythromycin, Simvastatin Ketoconazole (recent evidence that it is also a potent inhibitor of 2C8), Troleandomycin Cyclosporine... 

FIGURE 3.7 Chemical structure and IUPAC name of Simvastatin. 

All statins share an HMG-like moiety which is linked to rigid hydrophobic groups (Figure 12.3). Lovastatin and simvastatin are lactone prodrugs which are converted to the active open hydroxyl acid form in the hver. Enzyme studies show that the statins are competitive inhibitors of HMGR with respect to HMG-CoA and have K values in the 0.1-2.3 nM range [62]. Crystal structure studies have revealed that the statins occupy the active site where HMG-CoA binds but do not affect NADPH binding [63]. 

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. 

Three drugs, lovastatin. simvastatin, and pravastatin, cont-pn.se the list of approved HMG-CoA reductase inhihi(o l ol the treatment of hyperlipidemia in patients. The three dnipr have structures similar to the substrate. HMG-CoA. of ihr enzyme HMG-CoA reductase. Lovastatin and simvastatin arc lactones and pnxlrugs. activated by hydrnlysis in lb liver lo their respective )8-hydroxy acids. Pniva.slalin. in coti-irasl. is administered as the. stxlium salt of (he jS-hydroxv acid. 

Wilson SH, Herrmann J, Lerman LO, Holmes DR, Napoli C, Lerman A. 2002. Simvastatin preserves the structure of coronary adventitial vasa vasorum in experimental hypercholesterolemia in-dipendent of lipid lowering. Circulation 105 415-18... 

If two compounds have similar chemical structures, we tend to assume that they have similar solubilities. However, we should be cautious in making this assumption. Figure 2-6 shows the solubilities of lovastatin and simvastatin in a methanol/ water solvent system. Despite the fact that simvastatin has only one extra methyl group, the solubilities of the two compound are significantly different. 

Figure 2-6 Impact of chemical structure on the solubihty of lovastatin (compound 1) and simvastatin (compound 2) with one extra methyl group.

Solid compounds and sohd solutions are commonly encountered in optical isomers (Sheldon 1993). Solid compounds and sohd solutions can also exist in other structurally similar materials. Figure 2-22 shows the solubility of lovastatin and simvastatin in a solvent mixture of acetone/water. The solubilities of lovastatin and simvastatin vary, depending upon the composition in the solid phase. This is a solid solution similar to the one shown in Fig. 2-21. As we recall from Fig. 2-6, lovastatin and simvastatin differ by only one methyl group. Since lovastatin has lower solubility than simvastatin, the level of lovastatin will be higher in the solid phase, whereas the level of simvastatin will be higher in the liquid phase. 

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