Simvastatin

Statin drugs are some of the most effective drugs in the battle against high cholesterol. They are the most efficacious in lowering LDL cholesterol. Furthermore, recent studies have shown that statins are capable of preventing heart attacks and reducing the risk of strokes. However, statins are only recently gaining public attention though they have been available for many years.

Various cholesterol-lowering agents had been discovered during the 1950s and 1960s. However, the majority had unwanted side effects. In 1971, Drs. Akira Endo and Masao Kuroda began searching for a cleaner drug to treat hypercholesterolemia. Various experiments on animals and humans had shown that cholesterol could either be absorbed from the diet or synthesized de novo, when the diet lacked sufficient cholesterol. Additionally, cholesterol synthesis halted almost completely when the diet was cholesterol rich. Previous work had shown that cholesterol production within the body was controlled by a feedback mechanism in which cholesterol inhibited the enzyme b-hydroxy-b-methylglutaryl-CoA reductase (HMG Co-A reductase). By inhibiting this enzyme, the conversion of HMG-CoA to mevalonic acid was effectively blocked, and cholesterol synthesis was prevented (Figure 1). Drs. Endo and Kuroda, therefore, set forth attempting to discover a substance that would inhibit the action of HMG-CoA reductase.

Turning to the microbial world, the researchers hoped to identify a microorganism that produced an HMG-CoA reductase inhibitor as a defense mechanism against attack by other microbes, which rely on sterols as part of their biochemical make up. Initially, researchers looked for organisms with the ability to inhibit the incorporation of carbon-14 acetate into lipids. Broths that acted as inhibitors between acetate and lipid were then tested to see whether they would inhibit the production of lipids from tritium-labeled mevalonate. Broths which inhibited carbon-14 assimilation, but not lipid synthesis from labeled mevalonate, were believed to interfere in an early stage of cholesterol synthesis.

From these assays, two molds were identified as possible sources of the reductase inhibitor. Pythium ultimum, soil fungi that causes root rot, was found to produce a substance called Citrinin. Citrinin, an anti-fungal, irreversibly inhibits HMG Co-A reductase. The second mold that inhibited lipid synthesis was Penicillium citrinum, whose active compound was isolated by silica gel chromatography and crystallization. Further analysis lead to the discovery of a new compound now known as Mevastatin.

By 1976, the drug company Merck & Co. had become involved in the development of statins, and referencing Drs. Endo and Kuroda’s research, managed to successfully isolate a similar molecule, Lovastatin, from Aspergillus terreus. The new compound was slightly more effective as an HMG Co-A reductase inhibitor than mevastatin. By altering the chemical composition of the mevastatin molecule, various statin drugs were later created. Fluvastatin was synthetically derived from mevastatin by replacing the decalin ring of the fungal compounds with aromatic rings. Pravastatin was created through microbial alterations. Finally, synthetic alteration of the acyl group on C1 of mevastatin yields simvastatin, marketed commercially as Zocor (Gilson).

As the most publicized statin drug, boasting television and print ads, simvastatin – or Zocor as it is more commonly known – has come into the public’s attention as an important drug in treating hypercholesterolemia. It is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. Chemically, simvastatin is butanoic acid, 2,2-dimethyl-,1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S*-[1a,3a,7b, 8b (2S*,4S),-8ab]]. After oral ingestion, simvastatin, which is an inactive lactone form, is hydrolyzed to the corresponding b-hydroxyacid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol.

The production of mevalonic acid (a precursor to cholesterol) is brought about when HMG Co-A binds to the enzyme HMG Co-A reductase. After this has occurred, NADPH binds to the enzyme/substrate combination. A reaction then occurs in which NADPH is oxidized to NADP-CoA, and HMG Co-A is reduced to mevalonic acid. As the affinity of HMG Co-A reductase is substantially higher for simvastatin, it acts as a reversible competitive inhibitor to the enzyme reaction, and less mevalonic acid is produced in its presence. Thus, the cholesterol production pathway is broken (Figure 1).

The introduction of a competitive inhibitor for