■ 1 History

To the human body, cholesterol (2) is a Janus-faced molecule. On the one hand, it is an indispensable building block for life—about 23% of total body cholesterol resides in the brain, making up one-tenth of the solid substance of the brain. Red blood cell membranes are also rich in cholesterol, which helps stabilize the cell membranes and protect cells. Furthermore, cholesterol is also the precursor of hormones such as progesterone, testosterone, estrogen, and cortisol. On the other hand, cholesterol helps plaque buildup, which constricts or blocks arteries, leading to angina, heart attack, stroke, and many other cardiovascular diseases. To date, the experimental, genetic, and epidemiologic evidence all point to escalating cholesterol levels as a major risk factor for cardiovascular diseases. Other major risk factors include obesity, diabetes, hypertension, smoking, and inactive lifestyle.

Depending on different water-soluble carriers, cholesterol could have starkly opposing effects on the heart. Cholesterol in low-density lipoprotein (LDL), often known as “bad” cholesterol, is the fundamental carrier of blood cholesterol to body cells. It can slowly build up in the walls of the arteries feeding the brain and heart and can form plaques. In contrast, cholesterol in high-density lipoprotein (HDL), frequently dubbed “good” cholesterol, is a carrier that takes cholesterol away from the arteries and brings it to the liver, where it can be removed from circulation by metabolism. The higher the levels of HDL, the better. In general, women have higher levels of HDL, which may explain why women have longer life expectations than men. Their higher levels of estrogen are somehow correlated to higher HDL-cholesterol levels.

Many attempts have been made to lower cholesterol levels. In the 1950s and 1960s, estrogen was tried but was quickly abandoned because it caused feminizing side effects on men. Thyroid hormone also had unacceptable side effects, such as trembling. Resins such as cholestyramine were used as bile acid sequestrants, or bile acid binding resins. The approach was not popular in patients because they were difficult to swallow—literally. One of the early cholesterol-lowering drugs still in use today is nicotinic acid (3), which has been available since 1955.¹ When nicotinic acid is taken in milligram doses, it functions as a vitamin (vitamin B₃). When taken in gram doses, nicotinic acid’s cholesterol-lowering properties begin to manifest. It works through binding to a G protein-coupled receptor (GPCR) called “nicotinic acid receptor.” The nicotinic acid receptors, present not only in adipocytes but also in the spleen, are responsible for lowering LDL-cholesterol levels.² The advantage of nicotinic acid is that it also boosts the levels of HDL cholesterol. The disadvantage of nicotinic acid is that it often causes flushing as a side effect.

In 1954, Imperial Chemical Industries (ICI) discovered that clofibrate (4, Atromid-S) possessed significant cholesterol-lowering activity and marketed it in 1958.³ Parke-Davis’s gemfibrozil (5, Lopid), launched in 1982, was the second fibrate on the market. In order to find safer analogs of clofibrate (4), Parke-Davis screened over 8000 compounds similar to clofibrate using animals. Abbott’s fenofibrate (6, Tricor), is also a clofibrate analog. Fibrates have been found to be peroxisome proliferator-activated receptor-α (PPARα) agonists. Recent studies have also shown that the risk of drug-drug interactions (DDIs) increases 1,400-fold for statins if they are combined with fibrates. Therefore, fibrates should not be taken with statins.

The best class of cholesterol-lowering drugs are the statins, whose mechanism of action (MOA) is by inhibiting an enzyme in the liver called 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA, 7) reductase that promotes the rate-determining step (RDS) in cholesterol biosynthesis cascade. The first statin, mevastatin (Compactin, 8), was discovered by Akira Endo at Sankyo in Japan in 1973 after screening more than 6000 microbial strains. It is a secondary metabolite of the fungus Penicillium notatum. Sankyo conducted a clinical trial with mevastatin (8) in 1979 on patients with hypercholesterolemia, but terminated it a year-and-a-half later when intestinal tumors were observed in dogs given mevastatin (8) at large doses.

Merck was the first to bring a statin to the market in 1987 with their lovastatin (9, Mevacor). In 1974, Merck found a potent HMG-CoA reductase inhibitor in the 18th sample that they screened from a collection of soil cultures. The compound from the culture broth of the microorganism Aspergillus terreus was lovastatin (9). Further efforts to find a drug superior to lovastatin (9) were fruitless. Merck carried out semi-total synthesis of lovastatin and arrived at simvastatin (10, Zocor), which was 2.5 times more potent than lovastatin (9). Zocor’s sales peaked in 2003 with annual sales of $5.51 billion.

In 1991, Bristol-Myers Squibb (BMS) brought Endo/Sankyo’s pravastatin (11) to the US market with the trade name Pravachol. After dogs were given mevastatin (8), Pravachol was isolated from the urine. The dog’s liver enzyme CYP450 oxidized mevastatin to Pravachol. The fourth member of the statin class was fluvastatin sodium (12, Lescol) by Sandoz (now Novartis). It was the first statin on the market that was a totally synthetic drug. (That is, it was neither a natural product nor a semi-synthesized drug from a natural product.)

Atorvastatin calcium (1, Lipitor), the fifth statin to appear on the market, was also prepared by total synthesis. Discovered by scientists at Parke-Davis at the end of the 1980s, it was launched in 1996. It rapidly became the best-selling drug ever, becoming a blockbuster drug in the first year. By the time Lipitor’s patent expired at the end of 2011, it had generated over $130 billion in sales for Pfizer, which had acquired Parke-Davis/Warner-Lambert in 2000.

Bayer’s cerivastatin (13, Baycol) was launched in 1997 but was withdrawn in 2001 largely due to rhabdomyolysis (muscle weakness) stemming from its DDI issues. Cerivastatin is metabolized by CYP3A4, which is the same enzyme used by fibrates such as gemfibrozil (5, Lopid) for metabolism. Therefore, they are counterindicated and cannot be taken together. The final statin is AstraZeneca’s rosuvastatin (14, Crestor), which was introduced in 2003 in the United States. AstraZeneca licensed the drug from Shionogi in Japan.

■ 2 Pharmacology

2.1 Mechanism of Action

Cholesterol in the human body comes from two sources. One is from intestinal absorption of dietary cholesterol. The other source is cholesterol generated inside the body, primarily in the liver, to meet the body’s need if the diet is lacking sufficient cholesterol. The liver makes about 70% of the body’s cholesterol—three or four times more cholesterol than we get from diet on average. Statins lower cholesterol levels by inhibiting the hepatic HMG-CoA reductase.

In the early 1960s, Bloch elucidated the cholesterol biosynthesis pathway—the process by which the body makes cholesterol. The pathway involves the “acetic acid → squalene → cholesterol” cascade.⁴ An early step, which is also the slowest and thus the rate-limiting step, involves the reduction of HMG-CoA to mevalonate, which is then transformed into cholesterol after several additional steps. The crucial reduction process is accomplished by an enzyme called HMG-CoA reductase, which, in turn, is the rate-controlling enzyme in the biosynthetic pathway for cholesterol. Therefore, it is reasonable to believe that if one could block the function of HMG-CoA reductase, the chain reaction for cholesterol production would be suppressed.

HMG-CoA reductase is a polytopic, transmembrane protein that catalyzes a key step in the mevalonate pathway, which is involved in the synthesis of sterols, isoprenoids, and other lipids. Atorvastatin (1) binds tightly to the catalytic domain of the HMG-CoA reductase.⁵

2.2 Structure–Activity Relationship

Inspired by Merck’s patent on totally synthetic HMG-CoA reductase inhibitors such as diphenyl 15,⁶–⁸ medicinal chemists at Parke-Davis (led by Roth) sought to replace the hexahydronaphthalene core with heterocycles.⁹,¹⁰ Their initial efforts on 1,2,5-tri-substituted pyrroles (16) met with disappointment because of low potency. Overlapping pyrroles 16 with Merck’s diphenyl 15 quickly revealed that there was un-filled space at the 3- and 4-positions of pyrrole 16. Dibomopyrrole 17 (CI-957) was thus prepared and it was equipotent to lovastatin (9). Unfortunately, dibomopyrrole 17 was tested for use as an extremely potent rodenticide; it was immediately withdrawn from development due to serious concerns over its toxicities.

Table 1.1. The Structure-Activity Relationship (SAR) for Atorvastatin

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