Cholesterol compactin

Endo A. (1985) Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. J Med Chem 28 401 05. 

Another target, that at first seems to be unfavorable since it is principally common for all organisms, is the enzyme HMG-CoA-reduc-tase which is the regulatory enzyme in terpenoid biosynthesis. Results from trials with naturally produced inhibitors for that enzyme, such as Compactine and Mevinoline, indicate that these compounds are able to lower the cholesterol content in mammals, but not markedly depress sterol synthesis in fungi U3). 

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). 

Hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase is the rate-limiting enzyme in the cholesterol biosynthetic pathway (Fig. 1). In contrast to desmosterol and other late-stage lipid-soluble intermediates, HMG is water-soluble, and there are alternative metabolic pathways for its breakdown when HMG-CoA reductase is inhibited so that there is no buildup of potentially toxic precursors. Therefore, of the more than 30 enzymes involved in the biosynthesis of cholesterol, HMG-CoA reductase was a natural target. Substances that have a powerful inhibitory effect on this enzyme, including ML236B (compactin), were first discovered by Endo in a fermentation broth of Penicillium citrinum in the... 

Compactin was shown to lower plasma cholesterol in the rabbit (Watanabe et al., 1981), monkey (Kuroda et al., 1979), and dog (Tsujita et al., 1979). However, some investigators were led astray by the fact that compactin did not lower serum cholesterol in the rat (Fears et al.,... 

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... 

Bile acid binding resins have been the mainstay of treatment for heterozygous FH for many years. Unfortunately they are not as effective as one might hope, because the liver partially compensates for the drain on cholesterol by increasing its own production of cholesterol from acetyl-CoA (B51, Dll). Two recently developed drugs, compactin (B50, E7) and mevinolin... 

Octahydronapthalene synthesis.1 An intramolecular version of this annelation using a Michael addition to a vinyl sulfone provides the octahydronapthalene unit (1) of compactin (2), a mevinic acid of interest as an inhibitor of cholesterol synthesis. 

Compactin and rela- Aspergillus terreus, Monascus Cholesterol biosynthesis... 

The first "statin" was discovered by Endo and coworkers at Sankyo in Tokyo in 1976. After testing over 8,000 microbial extracts, they found a compound, named mevastatin (ML-236B) (Figure 9), from Penicillium citrinum which showed specific inhibition of HMG CoA reductase and functioned in vivo, lowering serum cholesterol levels. Further development of mevastatin was curtailed because inhibition of cholesterol biosynthesis was not restricted to the liver. The compound enters the lens and adrenals, where it blocks the essential biosynthesis of cholesterol. The same compound was also isolated by a team at the Beecham Research Laboratories in Brockham Park, Surrey. Whilst screening for antifungal activity, they isolated the compound, which they named compactin, from Pencillium brevicompactum, but apparently failed to recognise it as a potent inhibitor of HMG CoA reductase. 

The recently discovered title compound BMY-22089, 167, is more potent than the natural products compactin and mevinolin in lowering the serum cholesterol levels in both animals and man by inhibiting the action of enzyme, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) which determines the biosynthesis of cholesterol. It has been prepared in 20% overall yield in various steps starting with the tetrazol 168 (equation 58), for pharmacokinetic and drug distribution studies. 

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. 

An example of reversible ring closure is found with mevinolin and compactin that are both potent inhibitors of hydroxy-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), the rate-determining enzyme in the de novo biosynthesis of cholesterol. 

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. 

Figure 2. The mevalonic acid biosynthetic pathway. The transformation of hy-droxymethyl-coenzyme A (HMG-CoA) to mevalonic acid is the first committed step of the pathway. The enzyme, HMG-CoA reductase, catalyzes this step and is inhibited by the compounds, mevinolin and compactin. Note that farnesyl-pyrophosphate (Farnesyl-PP), the substrate of the protein, farnesyltransferase, can be used to make cholesterol or elongated to make geranylgeranyl-pyrophosphate (Geranylgeranyl-PP). The later compound is the substrate for the protein, geranylgeranyltransferase, or is further elongated to make the long-chain isoprenoids, dolichols, ubiquinones, and isoprenoic acids.

The identity of the multiple signals which regulate HMG-CoA reductase levels has yet to be established. One of these appears to be a sterol or sterol derivative. The second appears to be mevalonate or one of its metabolites [141]. Leading candidates for the sterol signal(s) are oxygenated derivatives of cholesterol. These are present in the circulation and many are potent suppressors of HMG-CoA reductase levels [175-177]. A candidate for the regulatory metabolite of mevalonate is isopentenyl adenine. Compactin added to baby hamster kidney-21 cells completely inhibits both DNA synthesis and cell proliferation [178]. Added mevalonolactone relieved this inhibition, but added sterols did not. Isopentenyl adenine also relieved compactin inhibition, and did so 100-200 times more effectively than did mevalonolactone [178]. 

Fomannosin (53), isolated from a wood-rotting fungus, has been synthesized in eleven steps from the cyclopentene (51) and the triester (52). ° Synthesis has been achieved from the dione (54) of an enzyme inhibitor called compactin (55), which has potential as a regulator of cholesterol bio-... 

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. 

The ability of Mevinolin and Compactin to block HMGCo reductase and hence cholesterol biosynthesis continues to stimulate the... 

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