NO-NSAIDs. Part 3: Nitric Oxide-Releasing Prodrugs of Non-steroidal Anti-inflammatory Drugs

摘要

In continuation of our efforts to discover novel nitric oxide-releasing non-steroidal anti-inflammatory drugs (NO-NSAIDs) as potentially “Safe NSAIDs,” we report herein the design, synthesis and evaluation of 21 new NO-NSAIDs of commonly used NSAIDs such as aspirin, diclofenac, naproxen, flurbiprofen, ketoprofen, sulindac, ibuprofen and indomethacin. These prodrugs have NO-releasing disulfide linker attached to a parent NSAID via linkages such as an ester (compounds 9 – 16 ), a double ester (compounds 17 – 24 ), an imide (compounds 25 – 30 ) or an amide (compounds 31 – 33 ). Among these NO-NSAIDs, the ester-containing NO-aspirin ( 9 ), NO-diclofenac ( 10 ), NO-naproxen ( 11 ), and the imide-containing NO-aspirin ( 25 ), NO-flurbiprofen ( 27 ) and NO-ketoprofen ( 28 ) have shown promising oral absorption, anti-inflammatory activity and NO-releasing property, and also protected rats from NSAID-induced gastric damage. NO-aspirin compound 25 , on further co-evaluation with aspirin at equimolar doses, exhibited comparable dose-dependent pharmacokinetics, inhibition of gastric mucosal prostaglandin E₂ (PGE₂) synthesis and analgesic properties to those of aspirin, but retained its gastric-sparing properties even after doubling its oral dose. These promising NO-NSAIDs could therefore represent a new class of potentially “Safe NSAIDs” for the treatment of arthritic pain and inflammation.