Atorvastatin Lipitor

Structural Formula

Ball-and-Stick Model

Structural Formula

= Carbon

Ball-and-Stick Model

Oxygen

= Hydrogen

Oxygen

Fluorine

Year of discovery: 1985; Year of introduction: 1997 (Pfizer); Drug category: Statins; Main uses: For the reduction of cholesterol levels (LDL) in blood and reducing the risk of cardiovascular disorders such as heart attack and stroke; Approximate number of people treated annually: Over 10 million; Related drugs: Lovastatin (Mevacor), Pravastatin (Pravachol), Simvastatin (Zocor), Fluvastatin (Lescol), Rosuvastatin (Crestor).

Cholesterol is a critical component of cell membranes in mammals and the precursor of all the steroid hormones. Although essential for the maintenance of normal cell function, this important substance also plays a role in the development of cardiovascular disease since elevated cholesterol levels in the blood correlate with arterial plaque formation. If left untreated, growth of such plaques can eventually cause heart attack or stroke. About 80% of the cholesterol in the body is synthesized internally, mainly in the liver; the remainder is dietary.

Research over many years for drugs that decrease circulating cholesterol led to the discovery of compounds now known as statins. The first of these, compactin, a naturally occurring compound produced by fungi, was discovered in 1976 by Dr. Akira Endo of Japan. A compound of similar structure, lovastatin, was approved by the FDA in 1987 and marketed as Mevacor by Merck.

Compactin ho1' v ^o Lovastatin (Mevacorâ„¢)

9 H3C

Compactin ho1' v ^o Lovastatin (Mevacorâ„¢)

These drugs inhibit the enzyme HMG-CoA reductase that plays a crucial role in cholesterol biosynthesis. Since cholesterol is not soluble in water, it is carried in the blood by water-soluble lipoproteins of two types, LDL and HDL. Low density lipoprotein (LDL), is sometimes called "bad cholesterol" since high levels of LDL in blood lead to plaque formation. On the other hand, high density lipoprotein (HDL) seems to protect the cardiovascular system.1,2 Since the early 1960s more than a dozen statins have been developed and commercialized, and currently many major pharmaceutical companies market a statin drug. The most widely used and potent statin, atorvastatin (Lipitorâ„¢), was first synthesized in 1985 by Dr. Bruce Roth in the US. This totally synthetic statin was introduced in 1997 and achieved sales of over $13 billion in 2006.

The complete three-dimensional structure of the enzyme HMG-CoA reductase which regulates the production of cholesterol has been determined with the inhibitor atorvastatin bound to the critical catalytic site (the location for normal substrate binding); a close-up view is shown below.3

1 Vascular Pharmacology 2007 46, 1-9; 2. Current Atherosclerosis Reports 2006. 8, 41-49; 3. Science 2001. 292, 1160-1164 (IHWK); Refs. p. 83

Arg590

Leu562

Leu853

Leu857

Atorvastatin

PART II. CHOLESTEROL-LOWERING AGENTS

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