Lovastatin structure

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

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. 

Microbial natural product chemistiy has generated a number of bioactive natural products. For instance cyclosporine A FK506 and rapamycin are used as immunosuppressants [16]. Other examples of microbial metabolites, having potential biomedical application include antihyperlipidemics, lovastatin and guggulsterone [17, 18]. The crude extracts of Mucor plumbeus exhibited acetylcholinesterase (AChE) enzyme inhibition activity. Our detailed chromatographic work on this crude extract resulted in the isolation of mucoralactone A (11), a novel steroid containing a lactone moeity incorporated in its structure. 

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 of HMG-CoA reductase. Top The HMG-CoA intermediate that is the immediate precursor of mevalonate, a critical compound in the synthesis of cholesterol. Bottom The structure of lovastatin and its active form, showing the similarity to the normal HMG-CoA intermediate (shaded areas). 

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... 

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. 

Serajuddin, A. T. M., S. Ranadive, and E. M. Mahoney. 1991. Relative lipophilicities, solubilities and structure-pharmacological considerations of HMG-CoA reductase inhibitors pravastatin, mevastatin, lovastatin and simvastatid.Pharm ScB0 830-834. 

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... 

Pravastatin (10) is another HMG-CoA reductase for the inhibition of cholesterol biosynthesis it is marketed by Sanyo and Bristol Myers Squibb under the trade names Mevalotin and Pravachol.87 It has a close structural relationship to lovastatin and simvastatin. It is produced by a two-step sequence. First, mevastatin (11), also known as ML-236B or compactin, is prepared by fermentation of Penicillium citrinum ss it is then enzymatically hydroxylated to produce 11 (Scheme 31.7).88-101... 

Lovastatin and mevastatin are synthesized via polyketide pathways. Polyketides are a large group of structurally diverse secondary metabolites produced by bacteria, fungi, and plants. The factors influencing production of lovastatin or mevastatin have not been fuUy elucidated. Studies of Aspergillus terreus grown in chemically defined media indicate that... 

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]. 

Lovastatin works by inhibiting 3-hydroxy-3-methylglutary 1 coenzyme A (HMG-(3oA) reductase, a key rate-limitingenzyme in the cholesterol biosynthetic pathway. However, the first specific inhibitors of this enzyme were discovered several years earlier by Endo et al. at Sankyo (157). The compounds, which are structurally related to lovastatin, were isolated from Penicillium citrinum and shown to block cholesterol synthesis in rats and lower cholesterol levels in the blood. Development of the most active compound, designated ML-236B (123), is believed to have been curtailed because of toxicity problems (158). 

Figure 26.22. Lovastatin, a Competitive Inhibitor of HMG-CoA Reductase. The part of the structure that resembles the 3-hydroxy-3-methylglutaryl moiety is shown in red.

HMG-CoA reductase is inhibited by the drug lovastatin, a natural product synthesized by a fungus (Figure 6.14), Lovastatin does not inhibit the enzyme directly it is converted to a compound (similar to the structure of HMG-CoA) that inhibits the enzyme. Ltivastatin, as well as several related compounds in a family of chemicals called statins, have found use in the treatment of cardiovascular disease throughout the world. The study outlined in Figure 6,15 shows the effectiveness of lovastatin in the treatment of cardiovascular disease. The drug lowers... 

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. 

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