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Science 22 May 1998:
Vol. 280. no. 5367, pp. 1268 - 1270
DOI: 10.1126/science.280.5367.1268
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Reports

Aspirin-like Molecules that Covalently Inactivate Cyclooxygenase-2

Amit S. Kalgutkar, Brenda C. Crews, Scott W. Rowlinson, Carlos Garner, * Karen Seibert, Lawrence J. Marnett dagger

Many of aspirin's therapeutic effects arise from its acetylation of cyclooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic effects result from its acetylation of COX-1. Here, aspirin-like molecules were designed that preferentially acetylate and irreversibly inactivate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hept-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as reactive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells and in the rat air pouch in vivo. Such compounds may lead to the development of aspirin-like drugs for the treatment or prevention of immunological and proliferative diseases without gastrointestinal or hematologic side effects.

A. S. Kalgutkar, B. C. Crews, S. W. Rowlinson, C. Garner, L. J. Marnett, A. B. Hancock Jr. Memorial Laboratory for Cancer Research, Vanderbilt Cancer Center, Center in Molecular Toxicology, Departments of Biochemistry and Chemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
K. Seibert, Searle/Monsanto, 800 North Lindbergh (T3G), St. Louis, MO 63167, USA.
*   Present address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

dagger    To whom correspondence should be addressed. E-mail: marnett{at}toxicology.mc.vanderbilt.edu

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