Aspirin-like Molecules that Covalently Inactivate Cyclooxygenase-2

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Science  22 May 1998:
Vol. 280, Issue 5367, pp. 1268-1270
DOI: 10.1126/science.280.5367.1268

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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 waso-(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.

  • * Present address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

  • To whom correspondence should be addressed. E-mail: marnett{at}

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