Bioisosteric Development of Multi-target Nonsteroidal Anti-inflammatory Drug - Carbonic Anhydrases Inhibitor Hybrids for the Management of Rheumatoid Arthritis.

Multi-target nonsteroidal anti-inflammatory drug (NSAID) - carbonic anhydrase inhibitor (CAI) agents for the management of rheumatoid arthritis are reported. The evidence of the plasma stability of the amide-linked hybrids previously reported prompted us to investigate their pain-relieving mechanism of action. A bioisosteric amide to ester substitution yielded a series of derivatives showing potent target CAs inhibition and to undergo cleavage in rat or human plasma depending to the NSAID portion. A selection of derivatives was assayed in vitro to indirectly evaluate their effect on COX-1 and COX-2. MD simulations demonstrated the entire hybrids are also able to efficiently bind the COX active site. In a rat model of RA, the most promising derivative (5c) showed a major antihyperalgesic action even than the equimolar coadministration of the single agents. The gathered data provided new insights on the action mechanism of these multi-target compounds, which induce markedly improved pain-relief than parent NSAIDs.

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