Discovery of HMG-CoA-Reductase Inhibitors Statins

One egg contains 300 mg of cholesterol, of which around 100 mg is produced dally by de novo synthesisin a hen. The supplementation of hen feed with 0.1 % of mevastatin reduces the egg s cholesterol content by around 10-15%. Laying hens make therefore a well-suited test model. [373] 

Out of 600 litres of fermentation broth, after repeated chromatography on sili-cagel and crystallisation, they isolated 23 milligrams of the active compound. Endo could show that mevastatin inhibits the incorporation of acetate, but not of mevalonate, into cholesterol. He eventually discovered that mevastatin competitively inhibits HMG-CoA-reductase (Fig. 5.151). 

With the structure determination of mevastatin in 1973, by a combination of degradation reactions. X-ray analysis and spectroscopic methods, the structural similarities to HMG-CoA were also recognised (Fig. 5.152). 

152 Mevastatin and iovastatin differ from each other only by one methyl group, which is of negligible importance for the pharmacological activity. 

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. 

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