Statins: Drug Stories-Part I

STATINS

Cholesterol was first isolated in 1784 from gallstones by French physician-chemist François Poulletier. French chemist Michel E. Chevreul named it cholesterine (solid bile in Greek: chole for bile and stereos for solid). The correct molecular formula for cholesterol was established in 1888 Austrian botanist Friedrich Reinitzer. It took more than two decades to decipher the complex structure of cholesterol. The credit for the same goes to Heinrich O. Wieland and Adolf Windaus who successfully established the structure through their brilliant work in early 1900s. Wieland was awarded the Nobel Prize in Chemistry in 1927 and Windaus in 1928.

Cholesterol became a molecule of interest in the etiology of atherosclerosis when in 1910 Windaus reported that atherosclerotic plaques from aortas of human subjects contained over 20-fold higher concentrations of cholesterol than did normal aortas! Through following a number of patients suffering from atherosclerosis, Norwegian clinician Carl Müller in 1939 described the genetic connection between cholesterol and heart attack. He reported that several large families in which high blood cholesterol levels and premature heart attacks together were inherited traits. Avedis K. Khachadurian in 1960s, after an extensive study, named this genetic condition the familial hypercholesterolemia (FH). He delineated two clinically distinct forms of FH in inbred families—the homozygous form (severe hypercholesterolemia at birth with plasma cholesterol levels of about 800 mg/dl) and heart attacks that occur as early as 5 years of age, and the heterozygous form, characterized by levels in the 300- to 400-mg/dl range and premature heart attacks that occur typically between 35 and 60 years of age. The genetic studies strongly suggested a causal relationship between cholesterol and atherosclerosis and coronary heart disease.

The Framingham Heart Study was carried out by National Heart Institute in Framingham, Massachutes, USA provided the first unequivocal evidence that individuals with higher blood cholesterol levels at the time of the baseline examination were more likely to experience a myocardial infarction in the subsequent years of follow-up. It is believed that the famed study was initiated due to the sudden death of US President, Franklin Roosevelt while still in office in 1945. The study highlighted the fact that the risk of heart attack was increased by a number of other factors such as high blood pressure and smoking.

This prompted scientist to design strategies to lower blood cholesterol levels. The searches began in the direction of lowering the absorption of cholesterol present in food and thus decrease contribution of exogenous cholesterol. The other strategy in focus was decreasing the biosynthesis of cholesterol in liver. In 1950s Konrad E. Bloch, Feodor Lynen, John Cornforth, and George Popják delineated the crucial steps in biosynthesis of cholesterol that involves about 30 enzymatic reactions.
Reduction of 3-hydroxy-3-methylglutaryl CoA to mevalonate is catalyzed by HMG-CoA reductase and is the rate limiting step. Thus, blocking this step seemed logical for arresting the biosynthesis of cholesterol.

In In 1971, inspired by Scientist Akira, Endo and his colleagues at Sankyo Research Laboratories began the project of using culture broths as a source of active compounds. After screening of 3800 strains of fungi, a culture broth of mold showed potent inhibitory activity against HMGCoA. The active principle turned out to be a known substance—citrinin. Citrinin strongly inhibited HMGCoA reductase and, furthermore, lowered serum cholesterol levels in rats. However, the team had to abandon the research because the compound was found to be of its toxic to the kidneys.

In 1972, a second active culture broth of blue-green mold, Penicillium citrinum Pen-51, was isolated from a rice sample collected at a grain shop in Kyoto. After a year of efforts, in July 1973, the team was able to isolate three active metabolites the culture broth. All three metabolites showed potent activity to inhibit cholesterol synthesis both in vitro and in vivo. However, the most active product of these three, called ML-236B or compactin, was used to further developmental study. Compactin

Compactin failed to show the desired effects in rats. It was found to activate HMG-CoA after repeated administration. This induction was found to be the main reason why compactin did not work in rats. These findings suggested that compactin would be effective in other animal species and patients with elevated blood cholesterol levels. However, compactin development was discontinued in 1980 when the drug was shown to cause lymphoma in dogs that received relatively high doses, 100 or 200 mg/kg/day for 2 years. Merck also initiated its own project on statins and and in February 1979 isolated a statin very similar to compactin in chemical structure, called mevinolin (lovastatin), from the fungus Aspergillus terreus. Lovastatin differed from compactin by an extra methyl group at 3^rd position.

Lovastatin

Lovastatin was found to effectively lower blood cholesterol levels and raise LDL receptors in liver in rats. After successful trials on humans, lovastatin in 1987 became the first statin to be commercially introduced for controlling blood cholesterol levels. The statins are structurally similar to the endogenous substrate HMG CoA and the mevaldyl CoA transition state intermediate. This enables them to inhibit the enzyme HMG CoA reductase.

Lovastatin was followed by a new statin, simvastatin. Sankyo, in turn, developed pravastatin and launched it in 1989. Four synthetic statins namely, fluvastatin, atorvastatin, pitvastatin and rosuvastatin were subsequently developed. Today the most popular statin is Pfizer’s atorvastatin (Lipitor®).

Pravastatin