Simvastatin enzyme activity

The discovery of compactin and lovastatin prompted efforts to develop derivatives with improved biological properties (163, 164). Modification of the methylbutyryl side chain of lovastatin led to a series of new ester derivatives with varying potency and, in particular, introduction of an additional methyl group a to the carbonyl gave a compound with 2.5 times the intrinsic enzyme activity of lovastatin (165). The new derivative, named simvastatin (124), was the second HMG-CoA reductase inhibitor to be marketed by Merck. Both lovastatin and simvastatin are prodrugs and are hydrolyzed to their active open-chain dihydroxy acid forms in the liver (166). A third compound, pravastatin (125), launched by Sankyo and Squibb in 1989, is the open hy-droxyacid form of compactin that was first identified as a urinary metabolite in dogs. Pravastatin is produced by microbial biotransformation of compactin. 

Inhibit Enzymes Many drugs are competitive inhibitors of key enzymes in pathways. The statin drugs (lovastatin, simvastatin), used to control blood cholesterol levels, competitively inhibit 3-hvdroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase in cholesterol biosynthesis. Methotrexate, an antineoplastic drug, competitively inhibits dihydrofolate reductase, depriving the cell of active folate needed for purine and deoxythymidine synthesis, thus interfering with DNA replication during S phase. 

The statins, lovastatin (L), simvastatin (S), pravastatin (P), fluvastatin (F), cerivastatin, and atorvastatin, inhibit HMG CoA reductase. The active group of L, S, P, and F (or their metabolites) resembles that of the physiological substrate of the enzyme (A). L and S are lactones that are rapidly absorbed by the enteral route, subjected to extensive first-pass extraction in the liver, and there hydrolyzed into active metabolites. P and F represent the active form and, as acids, are actively transported by a specific anion carrier that moves bile acids from blood into liver and also mediates the selective hepatic uptake of the mycotoxin, amanitin (A), Atorvastatin has the longest duration of action. 

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. 

FIGURE 6.7 The natural compounds compactin (mevastatin) and lovastatin block the cholesterol biosynthesis in inhibiting the enzyme HMG-CoA reductase. The later developed compounds simvastatin and pravastatin are semi-synthetic analogs. The open-ring derivative pravastatin is less lipophilic and therefore presents less central side effects. For all these compounds the ring-opened form is the actual active form in vivo. 

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. 

HMG-CoA reductase is the rate-determining enzyme of sterol synthesis, and its activity is regulated by competitive inhibition by compounds that bind to the same site as HMG-CoA. It is also regulated by substances that bind to other (allosteric) sites on the enzyme molecule. Inhibitors of this enzyme (e.g., simvastatin) are used as medicines to reduce cholesterol in patients whose cholesterol levels are too high. Through feedback inhibition, cholesterol is a strong inhibitor of the enzyme itself. No fungicides with this mode of action have yet been developed, but the possibility that they will be exists. 

The HMG-CoA reductase enzyme is stereoselective. The 3R,5R stereochemistry seen in the active forms of mevastatin and lovastatin (Fig. 30.8) is required for inhibitory activity and is present in all other HMGRIs. Stereochemistry of the substituehts on the bicyclic rings of lovastatin, simvastatin, and pravastatin is less crucial to activity, as indicated in the summary of the structure-activity relationships... 

Through-bond and through-space solid-state NMR correlation experiments including CP-INADEQUATE at natural isotope abundance have been applied by Brus and Jegorov to establish the structure and dynamic behaviour of simvastatin (C25H38O5), an active metabolite which inhibits 3-hydroxy-3-methyl-glutaryl coenzyme A, (HMG-CoA) reductase, the enzyme that is necessary in an early step of the cholesterol synthesis. 2D INADEQUATE spectroscopy has been applied by Meier et to establish the structures of a series of fullerene derivatives. 

Especially the inhibition or induction of cytochrome P450 subtype 3A4 (CYP 3A4) is clinically relevant, because a variety of active substances and food substances (e.g. grapefruit juice) are able to affect this enzyme. Substances inhibiting CYP 3A4 include ciclosporin, dihydropyridines, verapamil, midazolam, paclitaxel, simvastatin, lovastatin, atorvastatin, cimetidine, erythromycin, troleandomycin, ketoconazole (and other azoles). Substances inducing CYP 3A4 include steroids, rifampicin, phenobarbital and St John s wort. 

Lovastatin is rapidly metabolised, which is undesirable for any dmg likely to be chronically administered. In order to achieve once-daily dosing, steric hindrance around the ester carbonyl was increased by the introduction of an extra methyl group close to the ester bond in order to reduce the rate of esterase hydrolysis. This resulted in formation of simvastatin, a highly successful lipid-lowering agent. Simvastatin (like lovastatin) is inactive until metabolised in the liver to form its active metabolite mevinolinic acid (Fig. 8.48). Part of mevino-linic acid is stmcturally similar to the HMG portion of HMG-GoA, the substrate for HMG-CoA reductase, and hence competes with it for the active site of the enzyme. This reduces the amount of mevalonic acid which is produced. Mevalonic acid is a precursor of cholesterol. 

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