Research in The 1990s

Research in The 1990s: The Search for New Drugs

In 1763, the Reverend Edmund Stone took the first step toward the discovery of one of the most commonly used medicines when he noted that the bark of the English willow was an effective treatment for patients suffering from a fever. Stone explained the effect of willow bark by noting that ". . . many natural maladies carry their cures along with them, or their remedies lie not far from their causes." Thus, he argued, the English willow grows in the same moist regions where one was likely to catch the fever treated with its bark.

It took 50 years before the active ingredient in willow bark was isolated and named salicin, from the Latin name for the willow (Salix alba). Another 50 years elapsed before a large-scale synthesis for this compound was available. By that time, the compound was known as salicylic acid because saturated solutions in water are highly acidic (pH = 2.4).

By the end of the 19th century, salicylic acid was being used to treat rheumatic fever, gout, and arthritis. Many patients treated with this drug complained of chronic stomach irritation because of its acidity and the large doses (6-8 g/d) required. Because his father was one of these patients, Felix Hoffman searched the chemical literature for a less acidic derivative of salicylic acid. In 1898, Hoffman reported that the acetyl ester of salicylic acid was simultaneously more effective and easier to tolerate than the parent compound. He named this compound aspirin, taking the prefix a- from the name of the acetyl group and spirin from the German name of the parent compound spirsaure.

The existence of a drug that reduced both pain and fever initiated a search for other compounds that could achieve the same result. Although it was based on trial and error, this search inevitably produced a variety of substances, such as those in the figure below, that are analgesics, antipyretics, and/or anti-inflammatory agents. Analgesics relieve pain without decreasing sensibility or consciousness. Antipyretics reduce the body temperature when it is elevated. Anti-inflammatory agents counteract swelling or inflammation of the joints, skin, and eyes.


Salicylic acid		Acetylsalicylic acid (Aspirin)

Acetaminophen (Tylenol)		Ibuprofin (Motrin, Advil)

Although the use of aspirin has been widespread since the 19th century, the mechanism for its action was first described in 1971 [J. R. Vane, Nature, 231(25), 232-235 (1971)]. Vane noted that injury to tissue was often followed by the release of a group of hormones known as the prostaglandins, which have wide-spread physiological effects at very low concentrations. The prostaglandins regulate blood pressure, mediate the inflammatory response of the joints, induce the process by which blood clots, regulate the sleep/wake cycle, and, when appropriate, induce labor.

Vane suggested that aspirin and other nonsteroidal anti-inflammatory drugs (or NSAID's) inhibit the enzyme that starts the process by which prostaglandins such as PGE₂ and PGF₂ are synthesized from the 20-carbon unsaturated fatty acid known as arachidonic acid shown in the figure below. The steroidal anti-inflammatory drugs (such as hydrocortisone) achieve a similar effect by inhibiting the enzyme that releases arachidonic acid into the cell.



PGE₂		PGF_2a

Now that they are beginning to understand the mechanism by which drugs operate, medicinal chemists can approach the design of drugs by a rational process. A recent paper described progress toward the design of a drug to treat the debilitating diseases caused by protozoan parasites that afflict millions of people in Latin America, Africa, and Asia [W. N. Hunter, et al., Journal of Molecular Biology, 227, 1992, 322-333]. The potential target for this drug is an enzyme trypanothione reductase (TR) that protects the parasite from oxidative damage from the immune system of its mammalian host. Mammalian cells use a similar enzyme, known as glutathione reductase (GR), to protect against damage from oxidation reactions.

Hunter and coworkers found that the human GR enzyme has a smaller, more positively charged active site than the TR enzyme in the parasite. The structural information in this study can now be used to rationally modify a substrate of these enzymes until it possesses the following characteristics.

The substrate must be too large to bind to the GR enzyme in humans.
The substrate must have a high affinity for binding to the TR enzyme in the parasite.
The substrate must inhibit the activity of the TR enzyme, thereby allowing the immune system of the mammalian host to attack and eventually destroy the parasite.