Compactin, mevastatin

Lovastatin 10 (also known as mevinolin) is produced by A. terreus. The related compound compactin (mevastatin) 11, produced by Penicillium citrinum is identical to lovastatin apart... 

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. 

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 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. 

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. 

Pravastatin (CS-514) (19) has been produced by microbial transformation of mevastatin (compactin, ML-236B) [41,42]. Cytochrome P-450sca from Streptomyces carbophilus was described in detail as being responsible for this conversion [43]. It differs from lovastatin in that it contains a P-hydroxyl group at C-6 position of the hexahydronaphthalene ring. This modification makes it more hydrophilic than lovastatin. In... 

The development and use of HMGRIs began in 1976 with the discovery of mevastatin. Originally named compactin, this fungal metabolite was isolated from two different species of Penicillium and demonstrated potent, competitive inhibition of HMG-CoA reductase. Its affinity for the enzyme was shown to be 10,000-fold greater than that of the substrate HMG-CoA (22). Several years later, a structurally similar compound was isolated from Monascus ruber and Aspergillus terreus. This compound was originally known as... 

Mevastatin Compactin Antiojddant/anti- inflammatory, antithrombotic 23.0 Amarenco (2005), Vaughan(2003)... 

Like Sankyo, scientists at Beecham Pharmaceuticals in Britain were almost at the same time in search for new antibiotics and discovered mevastatin in the strain Penicillium brevicompactum being unaware of the earlier Japanese work, they named the compound compactin. [374] However, their efforts were narrowly focussed on antibiotics. While they used exclusively rats in their experimental animal models, the enormous potential of the compound, which they held in their hands, went unrecognised. 

Compactin (ML-268B, also known as mevastatin), produced by Pennicillium cit-rimm, is the 6-desmethyl analog of lovastatin (Figure 6.25). It is also an inhibitor of... 

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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