Aspirin-like molecules that covalently inactivate cyclooxygenase-2.

Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, Marnett LJ
Science. 1998 280 (5367): 1268-70

PMID: 9596581 · DOI:10.1126/science.280.5367.1268

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.

MeSH Terms (28)

Acetylation Acetylene Alkynes Animals Anti-Inflammatory Agents, Non-Steroidal Aspirin Binding Sites Cell Division Cell Line Colonic Neoplasms Cyclooxygenase 2 Cyclooxygenase 2 Inhibitors Cyclooxygenase Inhibitors Dinoprostone Drug Design Humans Indomethacin Isoenzymes Macrophages Membrane Proteins Mutagenesis, Site-Directed Prostaglandin-Endoperoxide Synthases Prostaglandin D2 Rats Rats, Inbred Lew Sulfides Thromboxane B2 Tumor Cells, Cultured

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