Simvastatin chemical structure

FIGURE 3.7 Chemical structure and IUPAC name of Simvastatin. 

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.

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.

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

F. 7.2 Chemical structures of statins. Rosuvastatin (Crestor) (a) simvastatin (Zocor) (b) pravastatin (Pravachol) (c) and pitavastatin (d)... 

Figure 8 Chemical structures of statins. HMG-CoA analog is highlighted with a dashed circle. Lovastatin and mevastatin are natural statins of fungal origin. Simvastatin and pravastatin are chemically modified derivatives of lovastatin and mevastatin, respectively. Fluvastatin, atorvastatin, cerivastatin (withdrawn from clinical use in 2001), pitavastatin and rosuvastatin are fully synthetic compounds (Schachter, 2005).

The discovery of these early statins paved the way for the worldwide development of other drugs based on the statin chemical structure (Figure 8.2). Sankyo and Merck directed their later efforts at manufacturing synthetic analogs. Many different statins are currently available for therapeutic use, but lovastatin and mevastatin remain the only fermentation-derived statins. The lovastatin biosynthetic pathway in A. terreus is well understood. This pathway was the first example of a polyketide synthetic pathway in which two fungal type I polyketide synthases work in combination to produce a product (Hendrickson et al., 1999 Kennedy et al., 1999). Since then several statins, including simvastatin, pravastatin, fluvastatin and atorvastatin, have been approved in many countries and are currently used by millions. 

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... 

Pravastatin and simvastatin are chemically modified derivatives of lovastatin. Atorvastatin, fluvastatin, and rosuvastatin are structurally distinct synthetic compounds. Statins exert their major effect—reduction of LDL levels—through a mevalonic acid-like moiety that competitively inhibits HMG-CoA reductase. By reducing the conversion of HMG-CoA to mevalonate, statins inhibit... 

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