Lovastatin and Compactin

Lovastatin (also known as mevinolin, monacolin K, mevastatin, andMevacor ) was isolated fiom Aspergillus terreus mdMonascus ruber [122-125]. It is used to reduce 

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HMG CoA reductase can be inhibited therapeutically by administering the drug lovastatin, based on the fungal products mevinolin and compactin, which competitively inhibit the enzyme and hence decrease the rate of cholesterol biosynthesis. Therefore, these compounds are routinely used for the treatment of hypercholesterolemia (high levels of blood cholesterol) (see Topic K6). 

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... 

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. 

Figure 6 5 Natural statins lovastatin, simvastatin, compactin, and pravastatin.

Lovastatin and six manufacturing impurities (compactin, asterric acid, lovastatin dimer, dehydrolovastatin, dihydrolovastatin, hydroxy acid lovastatin) were fiilfy resolved on a Cg column (2 = 200 nm for dihydrolovastatin and then 238 nm). A 14-min 60/40 -> 90/10 acetonitrile/water [0.1% H3PO4 at pH 2.2) gradient was used to generate the separation [1483]. A quantitation limit of 0.1% was reported. Four metabolites of lovastatin (6 / -hydroxy-, 3"-hydroxy-, 6 -oxomethylene-, and hydroxy acid lovastatin) were extracted from bile and liver tissues and baseline resolved from the parent compound using a C g column (X = 238 nm). Elution was complete in 25 min when a 30/70 -> 90/10 acetonitrile/water (5mM formic acid) gradient was used. Peak shapes were excellent [1484]. 

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. 

A promising natural product, compactin, was discovered in a screen of compounds from a fermentation broth from Fenicillium citrinum in a search for antibacterial agents. In some, but not all, animal studies, compactin was found to inhibit HMG-CoA reductase and to lower serum cholesterol levels. In 1982, a new HMG-CoA reductase inhibitor was discovered in a fermentation broth from Aspergillus cereus. This compound, now called lovastatin, was found to be structurally very similar to compactin, bearing one additional methyl group. 

In 1976, mevastatin (ML-236B, 6-demethylmevinolin) (2) was first reported as a potent competitive inhibitor of HMG-CoA reductase from the culture of Penicillium citrinum [23,24], which is identical with compactin, an antifungal compound isolated from P. brevicompactum [25,26]. Lovastatin (mevinolin, monacolin K) (3) has been isolated from the cultures of Aspergillus terreus [27] and Monascus ruber [28,29], separately. 

Compactin and lovastatin are natural statins used clinically under the trade names Zocor and Mevacor . Atorvastatin (Lipitor) , a synthetic statin, is now the most popular statin. Lipitor has greater potency and a longer half-life than natural statins have, because its metabolites are as active as the parent drug in reducing cholesterol levels. Therefore, smaller doses of the drug may be administered. The required dose is reduced further because Lipitor is marketed as a single enantiomer. In addition, it is more lipophilic than compactin and lovastatin, so it has a greater tendency to remain in the endoplasmic reticulum of the liver cells, where it is needed. 

Compactin (Fig. 10) was isolated from a microorganism as an inhibitor of HMG-CoA reductase (20). Compactin analogues such as lovastatin (Fig. 10), pravastatin and simvastatin are clinically used to reduce cholesterol in the body. 

The fungal metabolites compactin (97) and mevinolin (98) are potent inhibitors of cholesterol biosynthesis that target the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). Compounds of this type comprise a class called statins , of which 98, called Lovastatin, was the first to reach the market as a cholesterol-lowering agent in man. 

In 1978, using a different fungus, Merck discovered a substance that was nearly Identical to Endo s this one was named lovastatin. Merck held the U.S. rights and, in 1987, started marketing it in the United States as Mevacor, the first FDA-approved statin. Sankyo eventually gave up compactin and pursued another statin, which they licensed to Bristol-Myers Squibb, and it was sold as Pravachol. 

The first part will cover the role of fungal metabolites compactin and lovastatin in the inhibition of the enzymatic activity of HMGR [19], and the biological significance. 

Millions of people in the world suffer from cardiovascular disease, and it is a leading cause of death in both men and women. Elevation in plasma low-density lipoprotein (LDL) cholesterol levels is a major risk factor for myocardial infarction (heart attack) in these patients. Drugs to reduce dyslipidemia have included niacin and the fibrate class, but each of these has clinical limitations, such as low efficacy or toxic side effects. The development of HMG-CoA reductase inhibitors, or statins, has had an enormous clinical impact on the treatment of heart disease and prevention of heart attack, and these are taken by tens of millions of patients worldwide [1]. One of the first such drugs, lovastatin, was discovered in the 1970s as a fungal natural product [2] and lowered lipid levels in animals and healthy volunteers. Problems with the development of another early statin, compactin, halted advancement of lovastatin to regular clinical use until the late 1980s. Since then. 

Mevastatin (compactin) and lovastatin (mevinolin) are fungal fermentation products naturally produced by certain higher fungi. Mevastatin was first isolated by Akira Endo and co-workers in the 1970s from Penicillium citri-num Lovastatin is produced by Pleurotus ostreatus (oyster mushroom) and closely related to Pleurotus spp. as well as to Monascus purpureus (Chinese red yeast rice). Both mevastatin and lovastatin have a powerful inhibitory effect on HMG-CoA reductase. Discovered in the 1970s, they were taken into clinical development as potential dmgs... 

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