Nonsteroidal anti-inflammatory drugs: Exploiting bivalent COXIB/TP antagonists for the control of cardiovascular risk

Background. Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely prescribed or dispensed analgesics and antipyretics that act by inhibiting prostaglandins (PGs) and thromboxane synthesis. After the identification of a second isoform of COX, the pharmaceutical research focused on developing COX-2-selective drugs (COXIBs) considered as second generation NSAIDs that would retain the anti-inflammatory and analgesic activities of traditional NSAID without blunting the gastrointestinal cytoprotection sustained by COX1-derived products such as PGE2. However, while several clinical trials confirmed a gastrointestinal safer profile of COXIBs vs unselective COX inhibitors, increasing evidence for potential cardiovascular risk associated with COXIBs rapidly emerged. Today, there is no really safe NSAIDs to be used in chronic pain and anti-inflammatory treatments, as an adequate therapy associated with a minimal gastrointestinal damage and cardiovascular toxicity is yet to be developed. Objective. Here we present evidences that combining the anti-aggregating and anti-atherotrombotic activities of a thromboxane receptor antagonist with the anti-inflammatory activity of a COXIB we could obtain a new multitarget drug providing protection against the harmful activities mediated by the COXIB component, yet exploiting its recognized therapeutic advantages as a gastrointestinal-safer anti-inflammatory drug. We also summarize recent progress achieved in this field of research and possible new strategies to obtain a new bivalent compound. Conclusion. This possible third-generation NSAID with a safer pharmacological profile, will have all the pharmacological characteristics for the long-term therapy of chronic disorders such as inflammatory diseases or selected forms of cancer.