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Superaspirin Easy on Stomach

Researchers have made a new aspirin-like compound that promises to provide the same pain relief as aspirin, but without upset stomachs or the risk of kidney damage. The compound, described in tomorrow's Science, may also help reduce the risk of certain cancers and Alzheimer's disease.

This new "superaspirin" is one of about a dozen new compounds being developed that soothe aching joints by blocking the activity of an enzyme called COX-2, which helps promote inflammation, pain, and fevers. The problem with all aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) is that they also interfere with the activity of the COX-1 enzyme, which helps protect stomach lining and kidneys. Thus pharmaceutical companies have been eager to find drugs that target only COX-2, particularly since epidemiological data and now laboratory studies indicate the long-term use of these drugs can protect against colon cancer and Alzheimer's disease.

At least two companies, Monsanto Corp. in St. Louis, Missouri, and Merck and Co., based in Whitehouse Station, New Jersey, have tested COX-2 inhibitors in people and hope to be marketing their new superaspirin next year. "Eventually all those [NSAID] molecules on the market will become dinosaurs," predicts Philip Portoghese, a medicinal chemist at the University of Minnesota in Minneapolis.

So far, however, all of the new COX-2 inhibitors relieved pain for only as long as they were attached to COX-2. But now biochemist Lawrence Marnett of Vanderbilt University School of Medicine in Nashville, Tennessee, and his colleagues describe one that works much more like aspirin and chemically modifies COX-2, permanently blocking hormone production until the body makes more COX-2 enzyme.

To build the next generation of these selective inhibitors, Vanderbilt's Amit Kalgutkar and Marnett made a molecule that retains aspirin's original acetyl side group, which aspirin transfers to the COX-2 enzyme to destroy it. This new molecule also has a carbon ring attached to a sulfur atom, and a short string of carbon atoms hanging off the sulfur. They found it could reduce COX-2 activity by as much as existing temporary COX-2 inhibitors. Marnett, whose university has patented this class of permanent COX-2 inhibitors, hopes to team up with a pharmaceutical company to come up with an even more effective version of this new superaspirin.