Jie Jack Li - Top Drugs: History, Pharmacology, Syntheses

To the human body, cholesterol () is a Janus-faced molecule. On the one hand, it is an indispensable building block for lifeabout 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 swallowliterally. One of the early cholesterol-lowering drugs still in use today is nicotinic acid (), which has been available since 1955. 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 (, Atromid-S) possessed significant cholesterol-lowering activity and marketed it in 1958. Parke-Daviss gemfibrozil (, Lopid), launched in 1982, was the second fibrate on the market. In order to find safer analogs of clofibrate (), Parke-Davis screened over 8000 compounds similar to clofibrate using animals. Abbotts fenofibrate (, Tricor), is also a clofibrate analog. Fibrates have been found to be