Lovastatin acid, structure

Structure of lovastatin acid, a potent competitive inhibitor of HMG-CoA reductase. Note the similarity in structure of the red portion of the molecule with mevalonate, the product of the HMG-CoA reductase reaction. 

All HMGRIs can be chemically classified as 7-substituted-3,5-dihydroxyheptanoic acids, the general structure of which is shown in Table 30.3. Additionally, these compounds can be subclassitied based on their lower ring. Compounds structurally related to the natural products mevastatin and lovastatin have structural features common to ring A, whereas those that are completely synthetic have structural features common to ring B (25,27,28,29,30,31,32,33,34,35). 

The structures of (inactive) lovastatin, (active) mevinolinic acid, mevalonate, and synvinolin. 

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... 

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]. 

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. 

This high-value 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (4) is obtained from a fermentation. It is very similar in structure to lovastatin (see Section 3.2.9). A number of routes to various portions of the compound have been reported [3]. However, fermentation is used to provide the core structure and the dimethylbutyric acid side chain is enforced by coupling [8-10], although chemical methylation to form the quaternary dimethylated center has been achieved on synthetic intermediates [11,12]. 

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. 

A systematic investigation of structure-activity relationship (SAR) has shown that the introduction of an additional aliphatic group on the carbon a to the carbonyl group in a-methylbutyric acid ester linkage of lovastatin increases its potency. This result has led to the synthesis of simvastatin (15) and this modification increased the intrinsic inhibitory activity of lovastatin by 2.5 times [38]. 

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... 

Consistent with the structure, lovastatin exhibits no acid/base dissociation constants. Potentiometric titration of a sample in 50% aqueous methanol revealed no observable buffering action in the pH range of 2-11. 

Kaufman (32) has studied and determined the rate and equilibrium constants for the acid catalyzed hydrolysis of mevalonolactone, lovastatin and other structurally related HMG CoA reductase inhibitors in pH 2.0 buffer at 37°C. Under these conditions lactone concentrations decrease with time but do not approach zero indicating that the hydrolysis is reversible. The equilibrium nature of the reaction was further confirmed by repeating the experiment with hydroxyacid as starting material in the same system and demonstrating that an equilibrium composition is achieved that is identical to that achieved starting with lactone. Kinetic points in all studies were carried out to 15 hours and data obtained indicate that... 

The serum cholesterol-lowering agent mevinolin (lovastatin) is shown here. Identify the ester and lactone functional groups of lovastatin, and for each, write the structures of the carboxylic acid and alcohol from which the ester and lactone are formed. 

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