Mechanistic insights into COX irreversible inactivation by a new class of NO-donor aspirin-like molecules

NSAIDs are a widely used class of drugs endowed with anti-inflammatory, analgesic, antipyretic, and platelet anti-aggregatory properties. Their therapeutic effect is related to their ability to inhibit two cyclooxygenase isozymes, COX-1 and COX-2, responsible for production of prostanoids. Aspirin is unique among NSAIDs because it modifies both COX isoforms covalently by acetylating a serine residue (Ser530) located in the arachidonic acid-binding channel of the enzyme. We have recently realised a series of NO donor aspirin-like molecules in which the nitric oxide-releasing moieties have been joined to salicylic acid by an ester link to the phenol oxygen:1 Most of these compounds displayed in vivo anti-inflammatory activity similar to Aspirin, with reduced or no associated gastrotoxicity. In addition to NO-dependent vasodilator properties, NO independent platelet anti-aggregatory effects were observed. In this communication, the results of further in vitro pharmacological characterisation will be presented, showing that some derivatives behave as irreversible inhibitors of COX isozymes. The conclusions of a computational study aimed at throwing light on the possible structural basis of the irreversible enzyme inactivation will also be discussed.