Mevastatin and other Statins

Mevastatin (formerly compactin) (Figure 3.83) is produced by cultures of Penicillium citrinum and P. brevicompactum, and was shown to be a reversible competitive inhibitor of HMG-CoA reductase, dramatically lowering sterol biosynthesis in mammalian cell cultures and animals, and reducing total and low density lipoprotein cholesterol levels (see page 236). Mevastatin in its ring-opened form (Figure 3.84) mimics the half-reduced substrate mevaldate hemithioacetal during the two-stage reduction of HMG-CoA to mevalonate (see page 170), and the affinity of this agent towards HMG-CoA reductase is 10 000-fold more than the normal substrate. High blood cholesterol levels contribute to the incidence of coronary heart disease (see page 236), so mevastatin, or analogues, are of potential value in treating high risk coronary patients, and some agents are already in use. Although lowering of cholesterol levels reduces the risk of heart attacks, there is evidence that the beneficial effects of statins may extend beyond simply cholesterol reduction.

Lovastatin (formerly called mevinolin or monacolin K) (Figure 3.83) is produced by Monascus ruber and Aspergillus terreus and is slightly more active than mevastatin, but has been superseded by more active agents. Simvastatin is obtained from lovastatin by ester hydrolysis and then re-esterification, and is two to three times as potent as lovastatin. Pravastatin is prepared from mevastatin by microbiological hydroxylation using Streptomyces carbophilus and is consequently more hydrophilic than the other drugs, with an activity similar to lovastatin. Lovastatin and simvastatin are both lactones, and are inactive until metabolized

Mevastatin Hydrolysed Form

simvastatin pravastatin

R = H, mevastatin R = Me, lovastatin (mevinolin; monacolin K)

simvastatin

Figure 3.83

pravastatin

R = H, mevastatin R = Me, lovastatin (mevinolin; monacolin K)

Dihydroxy Carboxylic Acid

Figure 3.83

CO2H ,OH H

mevastatin (opened lactone form)

CO2H ,OH H

mevastatin (opened lactone form)

CO2H NADPH

CoAS HMG-CoA

CO2H NADPH

CoAS HMG-CoA

Figure 3.84

CO2H ,OH

CoAS

mevaldic acid hemithioacetal

CO2H O

mevaldic acid

NADPH

co2h

mevalonic acid in the liver to the open-ring hydroxy acids typified by pravastatin. Other agents currently in use are synthetic, though they feature the same dihydroxycarboxylic acid side-chain as in pravastatin. Atorvastatin, cerivastatin, and fluvastatin have all been introduced recently.

biosynthetic processes, though C-methylation must occur during chain assembly whilst activating carbonyl groups are available. The Diels - Alder reaction can then account for formation of the decalin system and further reactions will allow the other functional groups in lovastatin to be produced. The ester side-chain is derived as a separate unit from two acetates with a methyl from methionine, again with C-methylation preceding reduction processes. Lovastatin was isolated from cultures of Aspergillus terreus and was found to be a potent inhibitor of hydroxymethylglutaryl-CoA

(HMG-CoA) reductase, a rate-limiting enzyme in the mevalonate pathway (see page 169). Analogues of lovastatin (statins*) (Figure 3.83) find drug use as HMG-CoA reductase inhibitors, thus lowering blood cholesterol levels in patients.

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