ASPIRIN-LIKE MOLECULES THAT COVALENTLY INACTIVATE CYCLOOXYGENASE-2

Many of aspirin's therapeutic effects arise from its acetylation of cy clooxygenase-2 (COX-2), whereas its antithrombotic and ulcerogenic eff ects result from its acetylation of COX-1. Here, aspirin-like molecule s were designed that preferentially acetylate and irreversibly inactiv ate COX-2. The most potent of these compounds was o-(acetoxyphenyl)hep t-2-ynyl sulfide (APHS). Relative to aspirin, APHS was 60 times as rea ctive against COX-2 and 100 times as selective for its inhibition; it also inhibited COX-2 in cultured macrophages and colon cancer cells an d in the rat air pouch in vivo. Such compounds may lead to the develop ment of aspirin-like drugs for the treatment or prevention of immunolo gical and proliferative diseases without gastrointestinal or hematolog ic side effects.